Amido spirocyclic amide and sulfonamide derivatives

ABSTRACT

Provided are amido spirocyclic amide and sulfonamide compounds, pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.

FIELD OF THE INVENTION

The present invention relates to certain amido spirocyclic amide andsulfonamide compounds, pharmaceutical compositions comprising suchcompounds, and methods of treating cancer, including leukemias and solidtumors, inflammatory diseases, osteoporosis, atherosclerosis, irritablebowel syndrome, and other diseases and medical conditions, with suchcompounds and pharmaceutical compositions. The present invention alsorelates to certain amido spirocyclic amide and sulfonamide compounds foruse in inhibiting nicotinamide phosphoribosyltransferase (“NAMPT”).

BACKGROUND OF THE INVENTION

Nicotinamide adenine dinucleotide (NAD) plays a fundamental role in bothcellular energy metabolism and cellular signaling. NAD plays animportant role in energy metabolism, as the pyridine ring in the NADmolecule readily accepts and donates electrons in hydride transferreactions catalyzed by numerous dehydrogenases. The enzyme nicotinamidephosphoribosyltransferase (NAMPT, NMPRT, NMPRTase, or NAmPRTase,International nomenclature: E.C. 2.4.2.12), promotes the condensation ofnicotinamide with 5-phosphoribosyl-1-pyrophosphate to generatenicotinamide mononucleotide, which is a precursor in the biosynthesis ofNAD.

NAMPT is implicated in a variety of functions, including the promotionof vascular smooth muscle cell maturation, inhibition of neutrophilapoptosis, activation of insulin receptors, development of T and Blymphocytes, and reduction of blood glucose. Thus, small molecule NAMPTinhibitors have potential uses as therapies in a variety of diseases orconditions, including cancers involving solid and liquid tumors,non-small cell lung cancer, leukemia, lymphoma, ovarian cancer, glioma,breast cancer, uterine cancer, colon cancer, cervical cancer, lungcancer, prostate cancer, skin cancer, rhino-gastric tumors, colorectalcancer, CNS cancer, bladder cancer, pancreatic cancer and Hodgkin'sdisease. NAMPT inhibitors also have potential uses as therapies fordiseases or conditions such as cancer, rheumatoid arthritis, diabetes,atherosclerosis, sepsis, or aging.

Rongvaux et al. have demonstrated that NAMPT is implicated in theregulation of cell viability during genotoxic or oxidative stress, andNAMPT inhibitors may therefore be useful as treatments for inflammation.Rongvaux, A., et al. J. Immunol. 2008, 181, 4685-4695. NAMPT may alsohave effects on the reaction of endothelial cells to high glucoselevels, oxidative stress, and aging. Thus, NAMPT inhibitors may enableproliferating endothelial cells to resist the oxidative stress of agingand of high glucose, and to productively use excess glucose to supportreplicative longevity and angiogenic activity.

In particular, NAMPT inhibitors have been shown to interfere with NADbiosynthesis and to induce apoptotic cell death without any DNA damagingeffects or primary effects on cellular energy metabolism, and thus haveimportant anti-tumor effects. For example, the NAMPT inhibitor FK866 hasthese biochemical effects, and has also been shown to reduce NAD levels,induce a delay in tumor growth and enhance tumor radiosensitivity in amouse mammary carcinoma model. See, e.g., Hasmann M. and I. Schemainda,“FK866, a Highly Specific Noncompetitive Inhibitor of NicotinamidePhosphoribosyltransferase, Represents a Novel Mechanism for Induction ofTumor Cell Apoptosis,” Cancer Res. 2003, 63, 7436-7442; Drevs, J. etal., “Antiangiogenic potency of FK866/K22.175, a new inhibitor ofintracellular NAD biosynthesis, in murine renal cell carcinoma,”Anticancer Res. 2003, 23, 4853-4858.

More recently, another NAMPT inhibitor, CHS-828, has been shown topotently inhibit cell growth in a broad range of tumor cell lines. SeeOlesen, U. H. et al., “Anticancer agent CHS-828 inhibits cellularsynthesis of NAD,” Biochem. Biophys. Res. Commun. 2008, 367, 799-804;Ravaud, A. et al, “Phase I study and guanidine kinetics of CHS-828, aguanidine-containing compound, administered orally as a single doseevery 3 weeks in solid tumors: an ECSG/EORTC study,” Eur. J. Cancer2005, 41, 702-707. Both FK866 and CHS-828 are currently in clinicaltrials as cancer treatments.

There remains a need for potent NAMPT inhibitors with desirablepharmaceutical properties. Certain amido spirocyclic amide andsulfonamide derivatives have been found in the context of this inventionto have NAMPT-modulating activity.

SUMMARY OF THE INVENTION

In one aspect, the invention is directed to compounds of Formula I:

wherein:

-   R is    -   (a) an 8-, 9-, or 10-membered bicyclic heteroaryl comprising one        heteroatom selected from N, S, and O, and one, two, or three        additional N atoms, wherein said bicyclic heteroaryl is        unsubstituted or is substituted with one or more substituents        selected from the group consisting of deuterium, amino,        alkylamino, dialkylamino, alkyl, halo, cyano, haloalkyl,        hydroxy, hydroxyalkyl, and alkoxy, and wherein one or more N        atoms of said bicyclic heteroaryl is optionally an N-oxide; or    -   (b) a five- or six-membered nitrogen-linked heterocycloalkyl        ring fused to a phenyl or monocyclic five- or six-membered        heteroaryl, wherein said phenyl or heteroaryl is unsubstituted        or is substituted with one or more substituents selected from        the group consisting of deuterium, amino, alkylamino,        dialkylamino, alkyl, halo, cyano, haloalkyl, hydroxy,        hydroxyalkyl, and alkoxy; and-   R¹ is H, —(C₁₋₄alkylene)₀₋₁C(O)R^(a), —(C₁₋₄alkylene)₀₋₁CO₂R^(a),    —(C₁₋₄alkylene)₀₋₁S(O)R^(a), —(C₁₋₄alkylene)₀₋₁SO₂R^(a),    —C(O)NH(R^(a)), —C(O)N(R^(a))₂, or —C(O)C(O)NH(R^(a));    -   wherein each R^(a) is independently    -   (1) alkyl, unsubstituted or substituted with one or more R^(m)        substituents, wherein each R^(m) is independently selected from        the group consisting of deuterium, hydroxy, —NR^(b)R^(c),        alkoxy, cyano, halo, —C(O)alkyl, —CO₂alkyl, —CONR^(b)R^(c),        —S(O)alkyl, —SO₂alkyl, —SO₂NR^(b)R^(c), aryl, heteroaryl,        cycloalkyl, heterocycloalkyl, phenoxy, and —O-alkyl-OH;        -   wherein R^(b) is H or alkyl;        -   R^(c) is H, alkyl, alkoxyalkyl, haloalkyl, —C(O)alkyl,            —CO₂alkyl, —SO₂alkyl, —C(O)NH₂, or C(O)H; and        -   each aryl, heteroaryl, cycloalkyl, and heterocycloalkyl            group within R^(m) is unsubstituted or substituted with one            or more substituents independently selected from the group            consisting of alkyl, haloalkyl, hydroxy, —NR^(b)R^(c),            alkoxy, haloalkoxy, cyano, halo, oxo, —C(O)alkyl, —CO₂alkyl,            —C(O)-heterocycloalkyl, —CONR^(b)R^(c), —S(O)alkyl,            —SO₂alkyl, —SO₂-haloalkyl, —SO₂NR^(b)R^(c), aryl,            heteroaryl, cycloalkyl, and heterocycloalkyl; or two            substituents taken together form a fused phenyl, heteroaryl,            cycloalkyl, or heterocycloalkyl ring;            -   wherein each alkyl or alkoxy is unsubstituted or                substituted with —NR^(b)R^(c), heterocycloalkyl,                heteroaryl, or —C(O)alkyl; and            -   each aryl, heteroaryl, cycloalkyl, and heterocycloalkyl                is unsubstituted or substituted with alkyl, halo, oxo,                —C(O)alkyl;    -   (2) phenyl, cycloalkyl, heteroaryl, or heterocycloalkyl, each        unsubstituted or substituted with one or more R^(g)        substituents;        -   wherein each R^(g) is independently selected from the group            consisting of alkyl, haloalkyl, hydroxy, —NR^(b)R^(c),            alkoxy, haloalkoxy, cyano, halo, oxo, —C(O)alkyl, —CO₂alkyl,            —C(O)-heterocycloalkyl, —CONR^(b)R^(c), —S(O)alkyl,            —SO₂alkyl, —SO₂-haloalkyl, —SO₂NR^(b)R^(c), aryl,            heteroaryl, cycloalkyl, and heterocycloalkyl; or two R^(g)            substituents taken together form a fused phenyl, heteroaryl,            cycloalkyl, or heterocycloalkyl ring;            -   wherein each alkyl or alkoxy is unsubstituted or                substituted with phenyl, —NR^(b)R^(c), heterocycloalkyl,                heteroaryl, or —C(O)alkyl; and            -   each aryl, heteroaryl, cycloalkyl, and heterocycloalkyl                is unsubstituted or substituted with alkyl, halo,                —CO₂alkyl, or —C(O)alkyl; or    -   (3) —NR^(x)R^(y),        -   where R^(x) is H or alkyl; and        -   R^(y) is H, alkyl, alkoxyalkyl, haloalkyl, —C(O)alkyl,            —CO₂alkyl, or —SO₂alkyl;-   R² and R³ are each independently H or deuterium; and-   n is 1 or 2;-   and stereoisomers thereof, and pharmaceutically acceptable salts of    such compounds and stereoisomers.

In a further aspect, the invention relates to pharmaceuticalcompositions each comprising an effective amount of at least onecompound of Formula I or a pharmaceutically acceptable salt of acompound of Formula I. Pharmaceutical compositions according to theinvention may further comprise at least one pharmaceutically acceptableexcipient.

In another aspect, the invention is directed to a method of treating asubject suffering from a disease or medical condition mediated by NAMPTactivity, comprising administering to the subject in need of suchtreatment an effective amount of at least one compound of Formula I or apharmaceutically acceptable salt of a compound of Formula I, orcomprising administering to the subject in need of such treatment aneffective amount of a pharmaceutical composition comprising an effectiveamount of at least one compound of Formula I or a pharmaceuticallyacceptable salt of a compound of Formula I.

An aspect of the present invention concerns the use of compound ofFormula I for the preparation of a medicament used in the treatment,prevention, inhibition or elimination of cancer.

An aspect of the present invention concerns the use of a compound ofFormula I for the preparation of a medicament used in the treatment,prevention, inhibition or elimination of cancer, where the cancer can beselected from leukemia, lymphoma, ovarian cancer, breast cancer, uterinecancer, colon cancer, cervical cancer, lung cancer, prostate cancer,skin cancer, CNS cancer, bladder cancer, pancreatic cancer and Hodgkin'sdisease.

An aspect of the present invention concerns the use of a compound ofFormula I for the preparation of a medicament used in the treatment,prevention, inhibition or elimination of cancer, where the cancer can beselected from cancers with solid and liquid tumors, non-small cell lungcancer, leukemia, lymphoma, ovarian cancer, glioma, breast cancer,uterine cancer, colon cancer, cervical cancer, lung cancer, prostatecancer, skin cancer, rhino-gastric tumors, colorectal cancer, CNScancer, bladder cancer, pancreatic cancer and Hodgkin's disease.

In another aspect, the compounds of Formula I and pharmaceuticallyacceptable salts thereof are useful as NAMPT modulators. Thus, theinvention is directed to a method for modulating NAMPT activity,including when NAMPT is in a subject, comprising exposing NAMPT to aneffective amount of at least one compound of Formula I or apharmaceutically acceptable salt of a compound of Formula I.

In yet another aspect, the present invention is directed to methods ofmaking compounds of Formula I and pharmaceutically acceptable saltsthereof.

In certain embodiments of the compounds, pharmaceutical compositions,and methods of the invention, the compound of Formula I is a compoundselected from those species described or exemplified in the detaileddescription below, or is a pharmaceutically acceptable salt of such acompound.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

DETAILED DESCRIPTION AND PARTICULAR EMBODIMENTS

For the sake of brevity, the disclosures of the publications cited inthis specification, including patents and patent applications, areherein incorporated by reference in their entirety.

Most chemical names were generated using IUPAC nomenclature herein. Somechemical names were generated using different nomenclatures oralternative or commercial names known in the art. In the case ofconflict between names and structures, the structures prevail.

GENERAL DEFINITIONS

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings. If a definition is missing, the conventional definition asknown to one skilled in the art controls. If a definition providedherein conflicts or is different from a definition provided in any citedpublication, the definition provided herein controls.

As used herein, the terms “including”, “containing” and “comprising” areused in their open, non-limiting sense.

As used herein, the singular forms “a”, “an” and “the” include pluralreferents unless the context clearly dictates otherwise.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

DEFINITIONS

As used herein, “alkyl” refers to a saturated, straight- orbranched-chain hydrocarbon group having from 1 to 10 carbon atoms.Representative alkyl groups include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl, and the like, and longer alkyl groups, such asheptyl, octyl, and the like. As used herein, “lower alkyl” means analkyl having from 1 to 6 carbon atoms.

The term “alkoxy” as used herein includes —O-(alkyl), wherein alkyl isdefined above.

As used herein, “alkoxyalkyl” means -(alkylenyl)-O-(alkyl), wherein each“alkyl” is independently an alkyl group defined above.

The term “amino” as used herein refers to an —NH₂ group.

The term “alkylamino” as used herein denotes an amino group as definedabove wherein one hydrogen atom of the amino group is replaced by analkyl group as defined herein. Aminoalkyl groups can be defined by thefollowing general formula —NH-alkyl. This general formula includesgroups of the following general formulae: —NH—C₁-C₁₀-alkyl and—NH—C₁-C₆-alkyl. Examples of aminoalkyl groups include, but are notlimited to aminomethyl, aminoethyl, aminopropyl, aminobutyl.

The term “dialkylamino” as used herein denotes an amino group as definedabove wherein two hydrogen atoms of the amino group are replaced byalkyl groups as defined herein. Diaminoalkyl groups can be defined bythe following general formula —N(alkyl)₂, wherein the alkyl groups canbe the same or can be different and can be selected from alkyls asdefined herein, for example C₁-C₁₀-alkyl or C₁-C₆-alkyl.

“Aryl” means a mono-, bi-, or tricyclic aromatic group, wherein allrings of the group are aromatic. For bi- or tricyclic systems, theindividual aromatic rings are fused to one another. Exemplary arylgroups include, but are not limited to, phenyl, naphthalene, andanthracene.

“Aryloxy” as used herein refers to an —O-(aryl) group, wherein aryl isdefined as above.

“Arylalkyl” as used herein refers to an —O-(alkylenyl)-(aryl) group,wherein alkylenyl and aryl are as defined above. Non-limiting examplesof arylalkyls comprise a lower alkyl group. Non-limiting examples ofsuitable arylalkyl groups include benzyl, 2-phenethyl, andnaphthalenylmethyl.

“Arylalkoxy” as used herein refers to an —O-(alkylenyl)-aryl groupwherein alkylenyl and aryl are as defined above.

The term “cyano” as used herein means a substituent having a carbon atomjoined to a nitrogen atom by a triple bond.

The term “deuterium” as used herein means a stable isotope of hydrogenhaving one proton and one neutron.

The term “halogen” as used herein refers to fluorine, chlorine, bromine,or iodine. The term “halo” represents chloro, fluoro, bromo, or iodo.Halo can also denote chloro, fluoro, or bromo.

The term “haloalkyl” denotes an alkyl group as defined above wherein oneor more, for example one, two, or three of the hydrogen atoms of thealkyl group are replaced by a halogen atom, for example fluoro, bromo,or chloro, in particular fluoro. Examples of haloalkyl include, but arenot limited to, monofluoro-, difluoro-, or trifluoro-methyl, -ethyl or-propyl, for example, 3,3,3-trifluoropropyl, 2-fluoroethyl,2,2,2-trifluoroethyl, fluoromethyl, difluoromethyl, or trifluoromethyl,or bromoethyl or chloroethyl. Similarly, the term “fluoroalkyl” refersto an alkyl group as defined above substituted with one or more, forexample one, two, or three fluorine atoms.

The term “haloalkoxy” as used herein refers to an —O-(haloalkyl) groupwherein haloalkyl is defined as above. Exemplary haloalkoxy groups arebromoethoxy, chloroethoxy, trifluoromethoxy and 2,2,2-trifluoroethoxy.

The term “hydroxy” means an —OH group.

The term “hydroxyalkyl” denotes an alkyl group that is substituted by atleast one hydroxy group, for example, one, two or three hydroxygroup(s). The alkyl portion of the hydroxyalkyl group provides theconnection point to the remainder of a molecule. Examples ofhydroxyalkyl groups include, but are not limited to, hydroxymethyl,hydroxyethyl, 1-hydroxypropyl, 2-hydroxyisopropyl, 1,4-dihydroxybutyl,and the like.

The term “oxo” means an ═O group and may be attached to a carbon atom ora sulfur atom. The term “N-oxide” refers to the oxidized form of anitrogen atom.

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated, monocyclic, fused polycyclic, bridged polycyclic, or spiropolycyclic carbocycle having from 3 to 15 ring carbon atoms. A nonlimiting category of cycloalkyl groups are saturated or partiallysaturated, monocyclic carbocycles having from 3 to 6 carbon atoms.Illustrative examples of cycloalkyl groups include, but are not limitedto, the following moieties:

The term “cycloalkoxy” refers to a —O-(cycloalkyl) group.

“Heterocycloalkyl” as used herein refers to a monocyclic, or fused,bridged, or spiro polycyclic ring structure that is saturated orpartially saturated and has from 3 to 12 ring atoms selected from carbonatoms and up to three heteroatoms selected from nitrogen, oxygen, andsulfur. The ring structure may optionally contain up to two oxo groupson carbon or sulfur ring members. Heterocycloalkyl groups also includemonocyclic rings having 5 to 6 atoms as ring members, of which 1, 2, or3 ring members are selected from N, S, or O and the rest are carbonatoms. A “nitrogen-linked” heterocycloalkyl is attached to the parentmoiety via a nitrogen ring atom. A “carbon-linked” heterocycloalkyl isattached to the parent moiety via a carbon ring atom. Illustrativeheterocycloalkyl entities include, but are not limited to:

As used herein, the term “heteroaryl” refers to a monocyclic, or fusedpolycyclic, aromatic heterocycle having from three to 15 ring atoms thatare selected from carbon, oxygen, nitrogen, and sulfur. Suitableheteroaryl groups do not include ring systems that must be charged to bearomatic, such as pyrylium. Certain suitable 5-membered heteroaryl rings(as a monocyclic heteroaryl or as part of a polycyclic heteroaryl) haveone oxygen, sulfur, or nitrogen atom, or one nitrogen plus one oxygen orsulfur, or 2, 3, or 4 nitrogen atoms. Certain suitable 6-memberedheteroaryl rings (as a monocyclic heteroaryl or as part of a polycyclicheteroaryl) have 1, 2, or 3 nitrogen atoms. Examples of heteroarylgroups include, but are not limited to, pyridinyl, imidazolyl,imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl,benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, and furopyridinyl.

The term “bicyclic heteroaryl” refers to a heteroaryl as defined above,having two constituent aromatic rings, wherein the two rings are fusedto one another and at least one of the rings is a heteroaryl as definedabove. Bicyclic heteroaryls include bicyclic heteroaryl groupscomprising 1, 2, 3, or 4 heteroatom ring members and are unsubstitutedor substituted with one or more substituents selected from the groupconsisting of amino and halo; and wherein one or more N atoms of saidheteroaryl is optionally an N-oxide. Bicyclic heteroaryls also include8-, 9-, or 10-membered bicyclic heteroaryl groups. Bicyclic heteroarylsalso include 8-, 9-, or 10-membered bicyclic heteroaryl groups that have1, 2, 3 or 4 heteroatom ring members and that are unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of amino and halo; and wherein one or more N atoms of saidheteroaryl is optionally an N-oxide. Illustrative examples of bicyclicheteroaryls include, but are not limited to:

The term “five- or six-membered nitrogen-linked heterocycloalkyl ringfused to a phenyl or monocyclic heteroaryl, wherein said phenyl orheteroaryl is unsubstituted or is substituted with amino” include, butare not limited to, the following groups:

Those skilled in the art will recognize that the species of heteroaryl,cycloalkyl, and heterocycloalkyl groups listed or illustrated above arenot exhaustive, and that additional species within the scope of thesedefined terms may also be selected.

As used herein, the term “substituted” means that the specified group ormoiety bears one or more suitable substituents. As used herein, the term“unsubstituted” means that the specified group bears no substituents. Asused herein, the term “optionally substituted” means that the specifiedgroup is unsubstituted or substituted by the specified number ofsubstituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system.

As used herein, the expression “one or more substituents” denotes one tothe maximum possible number of substitution(s) that can occur at anyvalency-allowed position on the system. In a certain embodiment, one ormore substituents means 1, 2, 3, 4, or 5 substituents. In anotherembodiment, one or more substituent means 1, 2, or 3 substituents. Suchsubstituents may be the same or different from one another.

Any atom that is represented herein with an unsatisfied valence isassumed to have the sufficient number of hydrogen atoms to satisfy theatom's valence.

When any variable (e.g., alkyl, alkylenyl, heteroaryl, R¹, R², R^(a),etc.) appears in more than one place in any formula or descriptionprovided herein, the definition of that variable on each occurrence isindependent of its definition at every other occurrence.

Numerical ranges, as used herein, are intended to include sequentialwhole numbers. For example, a range expressed as “from 0 to 4” or “0-4”includes 0, 1, 2, 3 and 4.

When a multifunctional moiety is shown, the point of attachment to thecore is indicated by a line or hyphen. For example, aryloxy- refers to amoiety in which an oxygen atom is the point of attachment to the coremolecule while aryl is attached to the oxygen atom.

As used herein, the term “subject” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans; non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;and laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the presentinvention, the mammal is a human.

“Patient” includes both human and animals.

The term “inhibitor” refers to a molecule such as a compound, a drug, anenzyme activator, or a hormone that blocks or otherwise interferes witha particular biologic activity.

The term “modulator” refers to a molecule, such as a compound of thepresent invention, that increases or decreases, or otherwise affects theactivity of a given enzyme or protein.

The terms “effective amount” or “therapeutically effective amount” referto a sufficient amount of the agent to provide the desired biologicalresult. That result can be reduction and/or alleviation of the signs,symptoms, or causes of a disease or medical condition, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic use is the amount of a compound, or of acomposition comprising the compound, that is required to provide aclinically relevant change in a disease state, symptom, or medicalcondition. An appropriate “effective” amount in any individual case maybe determined by one of ordinary skill in the art using routineexperimentation. Thus, the expression “effective amount” generallyrefers to the quantity for which the active substance has atherapeutically desired effect.

As used herein, the terms “treat” or “treatment” encompass both“preventative” and “curative” treatment. “Preventative” treatment ismeant to indicate a postponement of development of a disease, a symptomof a disease, or medical condition, suppressing symptoms that mayappear, or reducing the risk of developing or recurrence of a disease orsymptom. “Curative” treatment includes reducing the severity of orsuppressing the worsening of an existing disease, symptom, or condition.Thus, treatment includes ameliorating or preventing the worsening ofexisting disease symptoms, preventing additional symptoms fromoccurring, ameliorating or preventing the underlying metabolic causes ofsymptoms, inhibiting the disorder or disease, e.g., arresting thedevelopment of the disorder or disease, relieving the disorder ordisease, causing regression of the disorder or disease, relieving acondition caused by the disease or disorder, or stopping the symptoms ofthe disease or disorder.

Additional Chemical Descriptions

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. For example, compounds of any formula given hereinmay have asymmetric or chiral centers and therefore exist in differentstereoisomeric forms. All stereoisomers, including optical isomers,enantiomers, and diastereomers, of the compounds of the general formula,and mixtures thereof, are considered to fall within the scope of theformula. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers. Allsuch isomeric forms, and mixtures thereof, are contemplated herein aspart of the present invention. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more tautomeric or atropisomericforms, and mixtures thereof.

Diastereomeric mixtures may be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers may beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride, orformation of a mixture of diastereomeric salts), separating thediastereomers and converting (e.g., hydrolyzing or de-salting) theindividual diastereomers to the corresponding pure enantiomers.Enantiomers may also be separated by use of chiral HPLC column. Thechiral centers of compounds of the present invention may be designatedas “R” or “S” as defined by the IUPAC 1974 Recommendations.

The compounds of the invention can form pharmaceutically acceptablesalts, which are also within the scope of this invention. A“pharmaceutically acceptable salt” refers to a salt of a free acid orbase of a compound of Formula I that is non-toxic, is physiologicallytolerable, is compatible with the pharmaceutical composition in which itis formulated, and is otherwise suitable for formulation and/oradministration to a subject. Reference to a compound herein isunderstood to include reference to a pharmaceutically acceptable salt ofsaid compound unless otherwise indicated.

Compound salts include acidic salts formed with inorganic and/or organicacids, as well as basic salts formed with inorganic and/or organicbases. In addition, where a given compound contains both a basic moiety,such as, but not limited to, a pyridine or imidazole, and an acidicmoiety, such as, but not limited to, a carboxylic acid, one of skill inthe art will recognize that the compound may exist as a zwitterion(“inner salt”), such salts are included within the term “salt” as usedherein. Salts of the compounds of the invention may be prepared, forexample, by reacting a compound with an amount of a suitable acid orbase, such as an equivalent amount, in a medium such as one in which thesalt precipitates or in an aqueous medium followed by lyophilization.

Exemplary salts include, but are not limited, to sulfate, citrate,acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate,phosphate, acid phosphate, isonicotinate, lactate, salicylate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucuronate,saccharate, formate, benzoate, glutamate, methanesulfonate (“mesylate”),ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate(i.e., 1,1′-methylene-bis(2-hydroxy-3-naphthoate)) salts. Apharmaceutically acceptable salt may involve the inclusion of anothermolecule such as an acetate ion, a succinate ion or other counterion.The counterion may be any organic or inorganic moiety that stabilizesthe charge on the parent compound. Furthermore, a pharmaceuticallyacceptable salt may have more than one charged atom in its structure.Instances where multiple charged atoms are part of the pharmaceuticallyacceptable salt can have multiple counterions. Hence, a pharmaceuticallyacceptable salt can have one or more charged atoms and/or one or morecounter ion.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

Additionally, acids and bases which are generally considered suitablefor the formation of pharmaceutically useful salts from pharmaceuticalcompounds are discussed, for example, by P. Stahl et al, Camille G.(eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use.(2002) Zurich: Wiley-VCH; S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, MD, available from FDA). These disclosures areincorporated herein by reference thereto.

Additionally, any compound described herein is intended to refer also toany unsolvated form, or a hydrate, solvate, or polymorph of such acompound, and mixtures thereof, even if such forms are not listedexplicitly. “Solvate” means a physical association of a compound of theinvention with one or more solvent molecules. This physical associationinvolves varying degrees of ionic and covalent bonding, includinghydrogen bonding. In certain instances the solvate will be capable ofisolation, for example when one or more solvent molecules areincorporated in the crystal lattice of a crystalline solid. “Solvate”encompasses both solution-phase and isolatable solvates. Suitablesolvates include those formed with pharmaceutically acceptable solventssuch as water, ethanol, and the like. In some embodiments, the solventis water and the solvates are hydrates.

One or more compounds of the invention may optionally be converted to asolvate. Methods for the preparation of solvates are generally known.Thus, for example, M. Caira et al., J. Pharmaceutical Sci., 93(3),601-611 (2004), describes the preparation of the solvates of theantifungal fluconazole in ethyl acetate as well as from water. Similarpreparations of solvates, hemisolvate, hydrates, and the like aredescribed by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). Atypical, non-limiting process involves dissolving the inventive compoundin a suitable amounts of the solvent (organic solvent or water or amixture thereof) at a higher than ambient temperature, and cooling thesolution at a rate sufficient to form crystals which are then isolatedby standard methods. Analytical techniques such as, for example,infrared spectroscopy, show the presence of the solvent (or water) inthe crystals as a solvate (or hydrate).

The invention also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula I, and treatment methods employing suchpharmaceutically acceptable prodrugs. The term “prodrug” means aprecursor of a designated compound that, following administration to asubject, yields the compound in vivo via a chemical or physiologicalprocess such as solvolysis or enzymatic cleavage, or under physiologicalconditions (e.g., a prodrug on being brought to physiological pH isconverted to the compound of Formula I). A “pharmaceutically acceptableprodrug” is a prodrug that is non-toxic, biologically tolerable, andotherwise suitable for formulation and/or administration to the subject.Illustrative procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

Examples of prodrugs include pharmaceutically acceptable esters of thecompounds of the invention, which are also considered to be part of theinvention. Pharmaceutically acceptable esters of the present compoundsinclude the following groups: (1) carboxylic acid esters obtained byesterification of the hydroxy groups, in which the non-carbonyl moietyof the carboxylic acid portion of the ester grouping is selected fromstraight or branched chain alkyl (for example, acetyl, n-propyl,t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl(for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl(for example, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di(C₆₋₂₄)acyl glycerol. Additional discussion ofprodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as NovelDelivery Systems (1987) 14 of the A.C.S. Symposium Series, and inBioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed.,American Pharmaceutical Association and Pergamon Press.

For example, if a compound of Formula I contains a carboxylic acidfunctional group, a prodrug can comprise an ester formed by thereplacement of the hydrogen atom of the acid group with a group such as,for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholine (C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula I contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula I incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R″-carbonyl, R″O-carbonyl,NR″R′-carbonyl where R″ and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇)cycloalkyl, benzyl, or R″-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N—(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

The present invention also relates to pharmaceutically activemetabolites of compounds of Formula I, and uses of such metabolites inthe methods of the invention. A “pharmaceutically active metabolite”means a pharmacologically active product of metabolism in the body of acompound of Formula I or salt thereof. Prodrugs and active metabolitesof a compound may be determined using routine techniques known oravailable in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997,40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767;Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984,13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985): andLarsen, Design and Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopically labelled compoundsare useful in metabolic studies (for example with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques[such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT)] including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or ¹¹C labeled compound may be particularly suitablefor PET or SPECT studies. Further, substitution with heavier isotopessuch as deuterium (i.e., ²H) may afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements. Isotopically labeledcompounds of this invention and prodrugs thereof can generally beprepared by carrying out the procedures disclosed in the schemes or inthe examples and preparations described below by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent.

The use of the terms “salt”, “solvate”, “polymorph”, “prodrug”, and thelike, with respect to the compounds described herein is intended toapply equally to the salt, solvate, polymorph, and prodrug forms ofenantiomers, stereoisomers, rotamers, tautomers, atropisomers, andracemates of the inventive compounds.

Compounds of the Invention

In some embodiments of Formula I, compounds of the invention have thefollowing Formula I-a:

wherein R, R¹, R², and R³ are as defined herein for Formula I.

In some embodiments, R is an unsubstituted or substituted bicyclicheteroaryl as defined for Formula I. In some embodiments, the bicyclicheteroaryl has 1, 2, or 3 nitrogen ring atoms. In other embodiments, thebicyclic heteroaryl is a 9- or 10-membered bicyclic heteroaryl,unsubstituted or substituted as described for Formula I. In otherembodiments, the bicyclic heteroaryl is an 8- or 9-membered heteroaryl,unsubstituted or substituted as described for Formula I. In otherembodiments, R is a bicyclic heteroaryl selected from the groupconsisting of:

each unsubstituted or substituted as described for Formula I. In furtherembodiments, R is selected from the group consisting of:

each unsubstituted or substituted as described for Formula I. In furtherembodiments, R is selected from the group consisting of:

In further embodiments, R is

In other embodiments, R is a five- or six-membered nitrogen-linkedheterocycloalkyl ring fused to an unsubstituted or substituted phenyl ormonocyclic heteroaryl, for examples a 6 membered heteroaryl, as definedin Formula I. In further embodiments, R is

In still other embodiments, R is

In other embodiments, R is substituted with one or more substituentsselected from the group consisting of amino and halo.

In some embodiments, R¹ is H. In other embodiments, R¹ is —C(O)R^(a),—CO₂R^(a), —S(O)R^(a), or —SO₂R^(a). In further embodiments, R¹ is—C(O)R^(a), —CO₂R^(a), or —SO₂R^(a). In other embodiments, R¹ is—C(O)NH(R^(a)) or —C(O)C(O)NH(R^(a)). In other embodiments, R^(a) isalkyl, unsubstituted or substituted as described for Formula I. In otherembodiments, R^(a) is —NR^(x)R^(y). In further embodiments, R^(a) is—CH₂C(O)R^(a) or —CH₂SO₂R^(a).

In some embodiments, R^(a) is methyl, ethyl, propyl, isopropyl,tert-butyl, isobutyl, isopentyl, phenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, pyrrolyl, furanyl, thiophenyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazoyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, isoindolinyl, azetidinyl, oxetanyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl,tetrahydropyranyl, or tetrahydrothiophenyl, each unsubstituted orsubstituted as described for Formula I. In other embodiments, R^(a) is abicyclic heteroaryl, unsubstituted or substituted with one or moresubstituents selected from the group consisting of alkyl,—CO2-tert-butyl, oxo, and halo. In other embodiments, R^(a) is alkyl,phenyl, benzyl, cycloalkyl, or heterocycloalkyl, each unsubstituted orsubstituted as described for Formula I. In some embodiments, R^(a) ismethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, 2,2-dimethylpropyl, hydroxyethyl, aminoethyl, cyanoethyl,ethoxy, tert-butoxy, phenyl, benzyl, cyclobutyl, cyclopentyl,cyclohexyl, oxetanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, ortetrahydropyranyl, each unsubstituted or substituted as described forFormula I. In other embodiments, R^(a) is tert-butoxy,2,2-dimethylpropyl, benzyl, cyclohexyl, tetrahydropyranyl, phenyl,methyl, ethyl, or isopropyl.

In some embodiments, R^(a) is phenyl, cycloalkyl, heteroaryl, orheterocycloalkyl, each unsubstituted or substituted as described forFormula I. In other embodiments, R^(a) is phenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, furanyl, thiophenyl,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazoyl,pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoindolinyl, azetidinyl,oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,tetrahydrofuranyl, tetrahydropyranyl, or tetrahydrothiophenyl, eachunsubstituted or substituted as in Formula I. In other embodiments,R^(a) is phenyl, cycloalkyl, heteroaryl, or heterocycloalkyl, eachunsubstituted or substituted with one or more substituents selected fromthe group consisting of fluoro, oxo, methyl, —CONH₂, acetyl, —SO₂methyl,—C(O)-isopropyl, pyridazinyl, triazolyl, dimethylaminomethyl, cyano,methyl-triazolyl-methoxy, trifluoromethoxy, pyrrolidinylmethyl,acetylamino, tetrazolylmethyl, methyl-tetrazolyl-methyl,methyl-imidazolyl-methyl, —NHSO₂methyl, 1,1-dioxothiomorpholinyl,4-methyl-piperazinylmethyl, —NHCONH₂, —SO₂CF₃, morpholinylmethyl,imidazolyl, —SO₂NH₂, methylpiperidinyl, methyl-piperazinyl,—C(O)(4-methyl-piperazinyl), morpholinyl, trifluoromethyl, cyclopropyl,ethyl, isoxazolyl, tetrazolyl, isopropyl, phenyl, fluoro-phenyl,tert-butyl, benzyl, N-methylpyrrolidinyl, N-acetyl-pyrrolidinyl,isobutyl, propyl, methylpyrazolyl, trifluoroethyl, pyrimidinyl, oxo,acetyl, cyano, —CO₂-tert-butyl, and amino.

In other embodiments, R¹ is alkyl, unsubstituted or substituted with oneor more substituents selected from the group consisting of fluoro,tert-butoxy, —C(O)NMe₂, —NHCHO, methoxy, phenoxy, cyano, acetyl,hydroxy, —OCH₂C(CH₃)═OH, —NH(acetyl), and —N(Me)(acetyl).

In other embodiments, R¹ is —SO₂R^(a), where R^(a) is methyl, ethyl,phenyl, benzyl, or 2,2-dimethylpropyl.

In other embodiments, R¹ is —C(O)NHR^(a), wherein R^(a) is methyl,ethyl, propyl, isopropyl, tertobutyl, cyclohexyl, —CH₂-cyclohexyl,oxetanyl, or methyloxetanyl, or R^(a) is a phenyl or benzyl group, eachoptionally substituted with one or more substituents selected from thegroup consisting of cyano, methyl, fluoro, methoxy, and chloro.

In some embodiments, one of R² and R³ is deuterium and the other is H.In other embodiments, both R² and R³ are H.

In some embodiments, each alkyl or alkylene described above isindependently a C₁₋₁₀alkyl. In other embodiments, each alkyl or alkylenein Formula I is independently a C₁₋₆alkyl. In still other embodiments,each alkyl or alkylene in Formula I is independently a C₁₋₄alkyl.

In certain embodiments, the compound of Formula I is chosen from thefollowing table:

Ex. Structure Chemical Name 1

tert-butyl 2-[(1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-8- azaspiro[2.5]octane-8-carboxylate 2

tert-butyl 2-[(thieno[2,3-c]pyridine- 2-carbonylamino)methyl]-8-azaspiro[2.5]octane-8-carboxylate 3

tert-butyl 2-[(imidazo[1,2-a]pyrimidine-6- carbonylamino)methyl]-8-azaspiro[2.5]octane-8-carboxylate 4

tert-butyl 2-[(furo[2,3-c]pyridine-2- carbonylamino)methyl]-8-azaspiro[2.5]octane-8-carboxylate 5

tert-butyl 2-[(imidazo[1,2-a]pyridine-6- carbonylamino)methyl]-8-azaspiro[2.5]octane-8-carboxylate 6

N-[[8-(3,3-dimethylbutanoyl)-8- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 7

N-[[8-(2-phenylacetyl)-8- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 8

tert-butyl 2-[(1H- pyrrolo[3,2-c]pyridine-2- carbonylamino)methyl]-8-azaspiro[2.5]octane-8-carboxylate 9

N-[[8-(cyclohexanecarbonyl)-8- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 10

N-[[8-(tetrahydropyran-4- carbonyl)-8-azaspiro[2.5]octan-2-yl]methyl]-1H- pyrrolo[3,2-c]pyridine-2- carboxamide 11

N-[(8-benzoyl-8-azaspiro[2.5]octan- 2-yl)methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 12

N-[[8-(2-methylpropanoyl)-8- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 13

N-[[8-(benzenesulfonyl)-8- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 14

N-[(8-ethylsulfonyl-8- azaspiro[2.5]octan-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 15

tert-butyl 2-[(1H-pyrazolo[3,4-b]pyridine-5- carbonylamino)methyl]-8-azaspiro[2.5]octane-8-carboxylate 16

N-[(8-acetyl-8-azaspiro[2.5]octan- 2-yl)methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 17

N-[(8-methylsulfonyl-8- azaspiro[2.5]octan-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 18

N-(8-azaspiro[2.5]octan-2-ylmethyl)- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide 19

N-(8-azaspiro[2.5]octan-2-ylmethyl)- 1H-pyrazolo[3,4-b]pyridine-5-carboxamide 20

N-[(8-propanoyl-8- azaspiro[2.5]octan-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridine- 2-carboxamide or 21

tert-butyl 2-((imidazo[1,2-a]pyridine- 6-carboxamido)methyl)-7-azaspiro[3.5]nonane-7-carboxylateor a pharmaceutically acceptable salt thereof, or a stereoisomer or apharmaceutically acceptable salt of said stereoisomer.

In certain other embodiments, the compound of Formula I is chosen fromthe following table:

Ex. Structure Chemical Name 22

tert-butyl 2-[(imidazo[1,2-a]pyridine-6- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate 23

tert-butyl 2-[(furo[2,3-c]pyridine-2- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate 24

N-[[6-(3,3-dimethylbutanoyl)- 6-azaspiro[2.5]octan-2- yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 25

tert-butyl 2-[(1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate 26

N-[[6-(2-imidazol-1-ylacetyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 27

N-[[6-(4,4,4-trifluorobutanoyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 28

N-[[6-[2-(3- methylsulfonylphenyl)acetyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 29

N-[[6-(3,3-dimethylbutanoyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 30

N-[[6-[2-(4-methylpiperazin-1- yl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 31

N-[[6-[2-(3- cyanophenyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 32

N-[[6-(2-cyclopropylacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 33

N-[[6-(2-pyrrolidin-1-ylacetyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 34

N-[[6-[2-(3-methylisoxazol-5- yl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 35

N-[[6-[2-(1-piperidyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 36

N-[[6-(2-tetrahydropyran-4- ylacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 37

N-[[6-(2-tetrahydrofuran-2- ylacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 38

N-[[6-(2-tert-butoxyacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 39

N-[[6-[2-(3-pyridyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 40

N-[[6-[2-[1-(2,2,2- trifluoroethyl)-4- piperidyl]acetyl]-6-azaspiro[2.5]octan-2- yl]methyl]-1H- pyrrolo[3,2-c]pyridine-2-carboxamide 41

tert-butyl 2-[(imidazo[1,2-a]pyridine-6- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate (isomer 1) 42

tert-butyl 2-[(imidazo[1,2-a]pyridine-6- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate (isomer 2) 43

tert-butyl 2-[(furo[2,3-c]pyridine-2- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate (isomer 1) 44

tert-butyl 2-[(furo(2,3-c]pyridine-2- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate (isomer 2) 45

N-[[6-(3,3-dimethylbutanoyl)- 6-azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 46

N-[[6-(3-methylbutanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 47

N-[[6-(2-phenylacetyl)-6- azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 48

tert-butyl 2-[(1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate (isomer 1)49

tert-butyl 2-[(1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate (isomer 2)50

N-[[6-(2-pyrazin-2-ylacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 51

N-[[6-(2-morpholinoacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 52

N-[[6-(2-tetrahydropyran-2- ylacetyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 53

N-[[6-(2-pyrrolidin-1- ylpropanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 54

N-[[6-[2-(tert-butylamino)-2- oxo-acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 55

N-[[6-[4-(dimethylamino)-4- oxo-butanoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 56

N-[[6-(1-methyl-5-oxo- pyrrolidine-3-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 57

N-[[6-[2-(2-oxopyrrolidin-1- yl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 58

N-[[6-(2,2- difluorocyclopropanecarbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 59

N-[[6-(tetrahydrofuran-3- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 60

N-[[6-(tetrahydropyran-4- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 61

N-[[6-(tetrahydrofuran-2- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 62

N-[[6-(2-formamidoacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 63

N-[[6-[3-(3,5-dimethylpyrazol- 1-yl)propanoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 64

N-[[6-(1- carbamoylpyrrolidine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 65

N-[[6-(3- morpholinopropanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 66

N-[[6-(1,1-dioxothiolane-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 67

N-[[6-[2-(3,5-dimethylpyrazol- 1-yl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 68

N-[[6-(1-acetylpyrrolidine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 69

N-[[6-(2- methylsulfonylbenzoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 70

N-[[6-[3-(1,2,4-triazol-4- yl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 71

N-[[6-[4- [(dimethylamino)methyl]benzoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 72

N-[[6-(4-acetamidobenzoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 73

N-[[6-(1- methylsulfonylpiperidine-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 74

N-[[6-(1- methylsulfonylpiperidine-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 75

N-[[6-(2-morpholinopropanoyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 76

N-[[6-(1- methylsulfonylpyrrolidine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 77

N-[[6-[2-(3-oxoisoindolin-1- yl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 78

N-[[6-(1-carbamoylpiperidine-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 79

N-[[6-(1-carbamoylpiperidine-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 80

N-[[6-[2-(1,1-dioxothiolan-3- yl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 81

N-[[6-[2-(2,4-dioxopyrimidin-1- yl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 82

N-[[6-(1-acetylpiperidine-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 83

N-[[6-[4-(tetrazol-1- ylmethyl)benzoyl]-6- azaspiro[(2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 84

N-[[6-[4- (methanesulfonamido)benzoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 85

N-[[6-[4-(1,1-dioxo-1,4- thiazinan-4-yl)benzoyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 86

N-[[6-[4-[(4-methylpiperazin-1- yl)methyl]benzoyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 87

N-[[6-[2-[(4-methylpiperazin-1- yl)methyl]benzoyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 88

N-[[6-[3-[(4-methylpiperazin- 1-yl)methyl]benzoyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 89

N-[[6-[3-(4-methylpiperazin- 1-yl)propanoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 90

N-[[6-(1-isopropyl-5-oxo- pyrrolidine-3-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 91

N-[[6-[2-(3-oxopiperazin-1- yl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 92

N-[[6-(3- methylsulfonylbenzoyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 93

N-[[6-(4- methylsulfonylbenzoyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 94

N-[[6-(4-ureidobenzoyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 95

N-[[6-[2-(4-acetylpiperazin-1- yl)acetyl]-6-azaspiro(2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 96

N-[[6-[4-[(5-methyltetrazol-1- yl)methyl]benzoyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 97

N-[[6-(pyridine-4-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 98

N-[[6-(pyridine-2-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 99

N-[[6-(oxazole-4-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 100

N-[[6-(1H-1,2,4-triazole-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 101

N-[[6-(1H-imidazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 102

N-[[6-(pyrimidine-4-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 103

N-[[6-(pyridine-3-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 104

N-[[6-(1H-pyrazole-3-carbonyl)- 6-azaspiro[2.5]octan-2-yl[methyl]furo[2,3-c]pyridine- 2-carboxamide 105

N-[[6-(1-methylimidazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 106

N-[[6-(3-methyl-1H-pyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 107

N-[[6-(2-methylpyrazole-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 108

N-[[6-(5-methyl-1H-pyrazole-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 109

N-[[6-(1-methylpyrazole-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 110

N-[[6-(pyridazine-3-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 111

N-[[6-(pyrimidine-5-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 112

N-[[6-(pyrazine-2-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 113

N-[[6-(pyridazine-4-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 114

N-[[6-(1-methylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 115

N-[[6-(1,5-dimethylpyrazole-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 116

N-[[6-(2,5-dimethylpyrazole-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 117

N-[[6-(5-methylisoxazole-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 118

N-[[6-(4-methyl-1,2,5- oxadiazole-3-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 119

N-[[6-(2-methylpyridine-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c)pyridine- 2-carboxamide 120

N-[[6-(4-methylpyridine-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 121

N-[[6-(2-methylpyridine-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 122

N-[[6-(5-methylpyrazine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 123

N-[[6-(3-cyclopropyl-1H- pyrazole-5-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 124

N-[[6-(1-ethyl-5-methyl-pyrazole- 4-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 125

N-[[6-(3,5-dimethylisoxazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 126

N-[[6-(1-ethylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 127

N-[[6-(6-cyanopyridine-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 128

N-[[6-(2,4-dimethyloxazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 129

N-[[6-(2-morpholinopyridine-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 130

N-[[6-(cyclopropanecarbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 131

N-[[6-[1-methyl-5- (trifluoromethyl)pyrazole-3-carbonyl]-6-azaspiro[2.5]octan- 2-yl]methyl]furo[2,3-c]pyridine-2-carboxamide 132

N-[[6-(4-isoxazol-5-yl-1-methyl- pyrazole-3-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 133

N-[[6-(2-acetamidopyridine-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 134

N-[[6-[3-(tetrazol-1-yl)-1H- pyrazole-4-carbonyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 135

N-[[6-(6-acetamidopyridine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 136

N-[[6-(3-ethyl-5-methyl- isoxazole-4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 137

N-[[6-(2-ethyl-5-methyl- pyrazole-3-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 138

N-[[6-(1-ethyl-3-methyl- pyrazole-4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 139

N-[[6-(3-methylisoxazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 140

N-[[6-[2-methyl-3-(3- methylpyrazol-1-yl)propanoyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 141

N-[[6-(1H-pyrazole-4-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 142

N-[[6-[2-(1-methylsulfonyl-4- piperidyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 143

N-[[6-(4-methylmorpholine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 144

N-[[6-[1-(2- methylpropanoyl)azetidine-3-carbonyl]-6-azaspiro[2.5]octan- 2-yl]methyl]furo[2,3-c]pyridine-2-carboxamide 145

N-[[6-(1-acetylazetidine-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 146

N-[[6-(1-pyridazin-3- ylpyrrolidine-3-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 147

N-[[6-[2-(1-pyrimidin-2-yl-4- piperidyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 148

N-[[6-[2-(1-isopropyl-4- piperidyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 149

N-[[6-[2-(1-methyl-4- piperidyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 150

N-[[6-[2-(3-methyloxetan-3- yl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]-1H- pyrrolo[3,2-c]pyridine- 2-carboxamide 151

isopropyl 2-[(1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6-carboxylate 152

N-[[6-[2-(2-cyanophenyl)acetyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 153

N-[[6-(3-methoxypropanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 154

N-[[6-[2-[4- (trifluoromethylsulfonyl)phenyl]acetyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2-carboxamide 155

N-[[6-[3- [acetyl(methyl)amino]propanoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 156

N-[[6-[2-(2-pyridyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 157

N-[[6-[(4- cyanophenyl)carbamoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 158

N-[[6-(m- tolylmethylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 159

N-[[6-(p-tolylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 160

N-[[6-(benzylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c)pyridine-2- carboxamide 161

N-[[6-[(2- fluorophenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 162

N-[[6-(p-tolylmethylcarbamoyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 163

N-[[6-[(4- fluorophenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 164

N-[[6-[(2- methoxyphenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl)methyl]furo[2,3-c]pyridine-2- carboxamide 165

N-[[6-[(3- methoxyphenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 166

N-[[6-[(3- fluorophenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 167

N-[[6-[(4- methoxyphenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 168

N-[[6-[(3,4- dichlorophenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 169

N-[[6-(1-adamantylcarbamoyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 170

N-[[6-[(4- chlorophenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 171

N-[[6-[(2- chlorophenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 172

N-[[6-(ethylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 173

N-[[6-[(2,4- dichlorophenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 174

N-[[6-[2-(3-hydroxy-3-methyl- cyclobutyl)acetyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 175

N-[[6-[2-(3-methyloxetan-3- yl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 176

N-[[6-[2-(2-pyridyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2- carboxamide 177

N-[[6-[2-(3-pyridyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2- carboxamide 178

N-[[6-[2-(3-cyanophenyl)acetyl]- 6-azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 179

N-[[6-[4-(1,2,4-triazol-1- yl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 180

N-[[6-[2-(2-methylimidazol-1- yl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 181

N-[[6-(1,3,5-trimethylpyrazole- 4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 182

N-[[6-(tert-butylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 183

N-[[6-(isopropylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 184

N-[[6- (cyclohexylmethylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 185

N-[[6-(propylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 186

N-[[6-(cyclohexylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 187

N-[[6-(phenylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 188

N-[[6-[2-(1-isopropyl-4- piperidyl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3- dihydropyrrolo[3,4-c]pyridine-2-carboxamide 189

N-[[6-(3-methylbutanoyl)-6- azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2- carboxamide 190

N-[[6-[2-(4-pyridyl)acetyl]-6- azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-e]pyridine- 2-carboxamide 191

N-[[6-(2-cyanoacetyl)-6- azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2- carboxamide 192

ethyl 2-[(1,3- dihydropyrrolo[3,4-c]pyridine- 2-carbonylamino)methyl]-6-azaspiro[2.5]octane-6-carboxylate 193

tert-butyl 2-[(1H- pyrrolo[3,2-c]pyridine-2- carbonylamino)methyl]-7-azaspiro[3.5]nonane-7-carboxylate 194

tert-butyl 2-[(furo[2,3-c]pyridine- 2-carbonylamino)methyl]-7-azaspiro[3.5]nonane-7-carboxylate 195

N-[[6-[2-(3-methyloxetan-3- yl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 196

N-[[6-(2-cyclohexylacetyl)-6- azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2- carboxamide 197

N-[[6-(3-cyclohexylpropanoyl)- 6-azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 198

N-[[6-(2-morpholinoacetyl)-6- azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2- carboxamide 199

N-[[6-(3-phenylpropanoyl)-6- azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 200

tert-butyl 2-[(1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-7- azaspiro[3.5]nonane-7- carboxylate 201

N-[[6-[2-(3,5- difluorophenyl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide 202

N-[[6-[2-[3- (trifluoromethyl)phenyl]acetyl]- 6-azaspiro[2.5]octan-2-yl)methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 203

N-[[6-(tert-butylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 204

[2,2,2-trideuterio-1,1- bis(trideuteriomethyl)ethyl] 2-[(1,3-dihydropyrrolo[3,4-c]pyridine- 2-carbonylamino)methyl]-6-azaspiro[2.5]octane-6-carboxylate 205

(2-methoxy-1,1-dimethyl-2- oxo-ethyl) 2-[(furo[2,3-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate 206

N-[[6-[2-(3- cyanophenyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 207

N-[[6-[2-(4-cyanophenyl)acetyl]- 6-azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 208

N-[[6-(phenylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 209

N-[[6-[3-(3-pyridyl)propanoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 210

N-[[6-(benzylcarbamoyl)-6- azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 211

N-[(6-benzylsulfonyl-6- azaspiro[2.5]octan-2- yl)methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 212

N-[[6-(tert-butylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 213

N-[[6-(3,3-dimethylbutanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide (isomer 1) 214

N-[[6-(3,3-dimethylbutanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide (isomer 2) 215

(2-hydroxy-1,1-dimethyl-ethyl) 2-[(furo[2,3-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate 216

N-[[6-[2-(4-cyanophenyl)acetyl]- 6-azaspiro[2.5]octan- 2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 218

(2-methoxy-1,1-dimethyl-ethyl) 2-[(1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6-carboxylate 219

N-[[6-(2-tetrahydropyran-4- ylacetyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 220

N-[[6-(1,3,5-trimethylpyrazole- 4-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 221

N-[[6-(1-methylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 222

N-[[6-(1-isopropyl-3,5-dimethyl- pyrazole-4-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 223

N-[[6-[1-(4-fluorophenyl)-3,5- dimethyl-pyrazole-4-carbonyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 228

(1-methylcyclobutyl) 2-[(1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6-carboxylate 229

N-[[6-(3-morpholinopropanoyl)- 6-azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2- carboxamide 230

N-[[6-(2,2-difluoro-2-phenyl- acetyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 231

N-[[6-(3-methylpyridine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 232

N-[[6-(3-methylpyridine-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 233

N-[[6-(6-methylpyridine-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 234

N-[[6-(6-methylpyridine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 235

N-[[6-(4-methylpyridine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 236

N-[[6-(1H-benzimidazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 237

N-[[6-(pyrrolo[1,2-c]pyrimidine- 3-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 238

N-[[6-(1H-benzotriazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 239

N-[[6-(1H-pyrrolo[2,3-b]pyridine- 4-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 240

N-[[6-(1H-indazole-4-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 241

N-[[6-(1H-benzimidazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 242

N-[[6-(4-cyanobenzoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 243

N-[[6-(3-cyanobenzoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 244

N-[[6-[4-[(5-methyl-1,2,4- oxadiazol-3-yl)methoxy]benzoyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 245

N-[[6-[4- (morpholinomethyl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 246

N-[[6-[4-[(2-methylimidazol-1- yl)methyl]benzoyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 247

N-[[6-[4- (trifluoromethoxy)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 248

N-[[6-[4-(pyrrolidin-1- ylmethyl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 249

N-[[6-[3-(1,2,4-triazol-1- ylmethyl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 250

N-[[6-[2-(1,2,4-triazol-1- ylmethyl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 251

N-[[6-[4-(1,2,4-triazol-1- ylmethyl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 252

N-[[6-[3-(imidazol-1- ylmethyl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 253

N-[[6-(4-imidazol-1-ylbenzoyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 254

N-[[6-[4-(1H-1,2,4-triazol-5- yl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 255

N-[[6-(6-imidazol-1-ylpyridine- 3-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2 carboxamide 256

N-[[6-[4- (trifluoromethyl)pyridine-2- carbonyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 257

N-[[6-[6- (trifluoromethyl)pyridine-3- carbonyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 258

N-[[6-(3-oxo-4H-1,4- benzoxazine-6-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 259

N-[[6-(4-sulfamoylbenzoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 260

N-[[6-[2-(imidazol-1- ylmethyl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 261

N-[[6-(quinoxaline-6-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 262

N-[[6-(1,6-naphthyridine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 263

N-[[6-(2-methyl-1H- benzimidazole-5-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 264

N-[[6-(3-acetamidobenzoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 265

N-[[6-(3-acetamidopyridine-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 266

N-[[6-(2,1,3-benzoxadiazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 267

N-[[6-(1,8-naphthyridine-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 268

N-[[6-(isoquinoline-5-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 269

N-[[6-(quinoxaline-2-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 270

N-[[6-(1,5-naphthyndine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 271

N-[[6-(1,8-naphthyridine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 272

N-[[6-(isoxazole-5-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 273

N-[[6-(3-methylbutanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 274

tert-butyl 2-[(4,6-dihydro-1H- pyrrolo[3,4-c]pyrazole-5-carbonylamino)methyl]-6- azaspiro[2.5]octane-6-carboxylate 275

N-[[6-[2-(1,4-dimethyl-4- piperidyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 276

N-[[6-[2-(3-hydroxy-3-methyl- cyclobutyl)acetyl]-6-azaspiro[2.5]octan-2- yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2-carboxamide 277

N-[[6-[2-(3-pyridyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 278

N-[[6-[2-(4-pyridyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 279

N-[[6-(1,3-dimethylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 280

N-[[6-[4-(2-methyltetrazol-5- yl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 281

N-[[6-(4,6-dimethylpyridine-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 282

N-[[6-(4-oxopentanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 283

N-[[6-(4-hydroxy-4-methyl- pentanoyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 284

N-[[6-(3-hydroxy-3-methyl- butanoyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 285

N-[[6-[2-(2-pyridyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 286

N-[[6-(2-pyrimidin-2-ylacetyl)- 6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2- carboxamide 287

N-[[6-(2-pyrazin-2-ylacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 288

N-[[6-(3-thiazol-2-ylpropanoyl)- 6-azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2- carboxamide 289

N-[[6-(2-phenoxyacetyl)-6- azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 290

N-[[6-(3-tetrahydropyran-4- ylpropanoyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 291

N-[[6-(4-methylpyridine-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1H- pyrrolo[3,2-c]pyridine-2- carboxamide 292

N-[[6-(3,5-dimethyl-1H- pyrazole-4-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide 293

N-[[6-(1,3,5-trimethylpyrazole- 4-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide 294

N-[[6-(1-tert-butyl-3,5-dimethyl- pyrazole-4-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 295

N-[[6-(1-benzyl-3,5-dimethyl- pyrazole-4-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 296

N-[[6-(5-tert-butyl-2-methyl- pyrazole-3-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 297

N-[[6-(2-ethylpyrazole-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 298

N-[[6-(2-tert-butyl-4-methyl- pyrazole-3-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 299

N-[[6-(2,4-dimethylpyrazole-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 300

N-[[6-(1,3,5-trimethylpyrazole- 4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo]2,3-c]pyridine-2- carboxamide (isomer 1) 301

N-[[6-(1,3,5-trimethylpyrazole- 4-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide (isomer 2) 302

N-[[6-(1H-indazole-3-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 303

N-[[6-[1-(1-isopropylpyrrolidin- 3-yl)pyrazole-4-carbonyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 304

N-[[6-[1-(1-acetylpyrrolidin-3- yl)pyrazole-4-carbonyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 305

N-[[6-[5-(1,3-dimethylpyrazol- 4-yl)isoxazole-3-carbonyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 306

tert-butyl 3-[2-[(furo[2,3-c]pyridine-2- carbonylamino)methyl]-6-azaspiro[2.5]octane-6-carbonyl]- 4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5- carboxylate 307

N-[[6-[1-(1-methylpyrrolidin-3- yl)pyrazole-4-carbonyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 308

N-[[6-(2-tert-butyl-5-methyl- pyrazole-3-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 309

N-[[6-(2- methylimidazo[1,2-a]pyridine- 3-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 310

N-[[6-(6-methyl-1H- benzimidazole-2-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 311

N-[[6-(5- methylimidazo[1,2-a]pyridine-2-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2-carboxamide 312

N-[[6-(6-fluoro-1H-indazole-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 313

N-[[6-(pyrazolo[1,5-a]pyrimidine- 2-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 314

N-[[6-(1-ethyl-3,5-dimethyl- pyrazole-4-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 315

N-[[6-(6- methylimidazo[1,2-a]pyridine- 2-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 316

N-[[6-(pyrazolo[1,5-a]pyridine- 3-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 317

N-[[6-(imidazo[1,2-a]pyridine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 318

N-[[6-(5-isopropylisoxazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 319

N-[[6-(3-isobutyl-1H-pyrazole- 5-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 320

N-[[6- (imidazo[1,2-a]pyrimidine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 321

N-[[6- (pyrazolo[1,5-a]pyrimidine-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 322

N-[[6-(3-tert-butyl-1H-pyrazole- 5-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 323

N-[[6-(5-isopropyl-1H-pyrazole- 3-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 324

N-[[6-(3-isopropyl-1H-pyrazole- 4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 325

N-[[6-(2-isopropylpyrazole-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 326

N-[[6-(5-ethyl-2-methyl- pyrazole-3-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 327

N-[[6-(5-cyclopropylisoxazole- 3-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 328

N-[[6-(5-cyclopropylisoxazole- 4-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 329

N-[[6-(3,5-dimethyl-1H-pyrazole- 4-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 330

N-[[6-(1,5-dimethylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 331

N-[[6-(4-methyloxazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 332

N-[[6-(3-cyclopropyl-1H- pyrazole-4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 333

N-[[6-(1,4,5,6- tetrahydrocyclopenta[c]pyrazole- 3-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide 334

N-[[6-(2,5-dimethyloxazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 335

N-[[6-(1,3-dimethylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 336

N-[[6-(oxazole-5-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 337

N-[[6-(isoxazole-4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 338

N-[[6-(1H-imidazole-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 339

N-[[6-[4-(4-methylpiperazin-1- yl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 340

N-[[6-(3H- imidazo[4,5-b]pyridine-6- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 341

N-[[6-(5-methylpyridine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 343

N-[[6-[4-[(4-methylpiperazin-1- yl)methyl]benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide 344

N-[[6-[3-[(4-methylpiperazin-1- yl)methyl]benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide 345

N-[[6-[4- [(dimethylamino)methyl]benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide 346

N-[[6-[4-[(4-methylpiperazin-1- yl)methyl]benzoyl]-6-azaspiro[2.5]octan-2- yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2-carboxamide 347

N-[[6-(1,5-dimethylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 348

N-[[6-(2,2- dimethylcyclopropanecarbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide 350

(3-methyloxetan-3-yl) 2-[(1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6-carboxylate 351

(2-hydroxy-1,1-dimethyl-ethyl) 2-[(1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate 352

N-[[6-(4-methylpyridine-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 353

N-[[6-(3-cyclopropyl-1H-pyrazole- 5-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 354

N-[[6-(4-isoxazol-5-yl-1-methyl- pyrazole-3-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide 355

N-[[6-(2,4-dimethyloxazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 356

N-[[6-[2-(1,4-dimethyl-4- piperidyl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide 357

N-[[6-[2-(2- cyanophenyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 358

(2-acetamido-1,1-dimethyl- ethyl) 2-[(1,3-dihydropyrrolo[3,4-c]pyridine-2- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate 359

N-[[6-(2-thiazol-2-ylacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 360

N-[[6-(4-hydroxy-4-methyl- pentanoyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 361

N-[[6-[(3-methyloxetan-3- yl)carbamoyl]-6- azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 362

N-[[6-[4-(4-methylpiperazin-1- yl)benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 363

N-[[6-[4-(4-methylpiperazin-1- yl)benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide 364

N-[[6-(2,2- dimethylcyclopropanecarbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide 365

N-[[6-(1,3,5-trimethylpyrazole- 4-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide(isomer 1) 366

N-[[6-(1,3,5-trimethylpyrazole- 4-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine- 2-carboxamide (isomer2) 367

tert-butyl 2-[[(1,1,3,3- tetradeuteriopyrrolo[3,4-c]pyridine-2-carbonyl)amino]methyl]-6- azaspiro[2.5]octane-6-carboxylate 368

N-[[6-(3-cyclopropyl-1H- pyrazole-5-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide 369

N-[[6-(4-isoxazol-5-yl-1-methyl- pyrazole-3-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide 370

N-[[6-(2,4-dimethyloxazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1H- pyrrolo[3,2-c]pyridine-2- carboxamide 371

N-[[6-(2,2- dimethylcyclopropanecarbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 372

N-[[6-[4-(4-methylpiperazine- 1-carbonyl)benzoyl]-6-azaspiro[2.5]octan-2- yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2-carboxamide 373

N-[[6-(2,2- dimethylcyclopropanecarbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 375

(3-methyltetrahydrofuran-3-yl) 2-[(1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6-carboxylate 376

(2-hydroxy-2-methyl-propyl) 2-[(1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6-carboxylate 377

N-[[6-(2,2- dimethylcyclopropanecarbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 378

N-[[6-(2,2- dimethylpropylsulfonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide 379

N-[[6-(2,2- dimethylpropylsulfonyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide 381

N-[[6-(2,2- dimethylpropylsulfonyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 382

N-[[6-(4,4,4-trifluorobutanoyl)- 6-azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 383

tert-butyl 2- [(pyrazolo[1,5-b]pyridazine-5- carbonylamino)methyl]-6-azaspiro[2.5]octane-6-carboxylate 384

N-[[6-(2,4-dimethyloxazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide (single isomer) 385

N-[[6-(2,4-dimethyloxazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide 387

N-[[6-[2-(2-hydroxy-2-methyl- propoxy)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide 388

N-[[6-[2-methyl-4- (trifluoromethyl)thiazole-5-carbonyl]-6-azaspiro[2.5]octan- 2-yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 389

N-[[6-(2,2- dimethylcyclopropanecarbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 392

tert-butyl 2- [(imidazo[1,2-a]pyridin-6- ylmethylcarbamoylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate 393

N-[[6-[2-(2-hydroxy-2-methyl- propoxy)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide 394

N-[[6-[2-(6-amino-3- pyridyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 395

N-[[6-(morpholine-4-carbonyl)- 6-azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 396

N-[[6-[5-(trifluoromethyl)-1H- pyrazole-3-carbonyl]-6-azaspiro[2.5]octan-2- yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2-carboxamide 397

N-[[6-(4-hydroxy-4-methyl- pentanoyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1H- pyrrolo[3,2-c]pyridine-2- carboxamide 398

N-[[6-[4- (trifluoromethyl)pyridine-3- carbonyl]-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 399

N-[[6-[2-(4- methyltetrahydropyran-4- yl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 400

N-[[6-[2-(3-hydroxy-3-methyl- cyclobutyl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide 401

(2-hydroxy-2-methyl-propyl) 2- [(1H-pyrrolo[3,2-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6-carboxylate 402

tert-butyl 2-[(imidazo[1,2-b]pyridazine-6- carbonylamino)methyl]-6-azaspiro[2.5]octane-6-carboxylate 403

N-[[6-[2-[4-methyl-1-(2,2,2- trifluoroethyl)-4-piperidyl]acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide 404

N-[[6-(2,4-dimethylthiazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 405

N-[[6-[4-(1-methyl-4- piperidyl)benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide 406

tert-butyl 2-[[(6-amino-1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonyl)amino]methyl]-6- azaspiro[2.5]octane-6-carboxylate 407

N-[[6-(2-pyrimidin-5-ylacetyl)- 6-azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2- carboxamide 408

1,1,3,3-tetradeuterio-N-[[6-(3- methylbutanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]pyrrolo[3,4-c]pyridine- 2-carboxamide 409

(3-methyloxetan-3-yl) 2-[[(1,1,3,3- tetradeuteriopyrrolo[3,4-c]pyridine-2-carbonyl)amino]methyl]-6- azaspiro[2.5]octane-6-carboxylate 410

1,1,3,3-tetradeuterio-N-[[6-(2,4- dimethyloxazole-5-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyrrolo[3,4-c]pyridine- 2-carboxamide411

N-[(6-benzoyl-6- azaspiro[2.5]octan-2- yl)methyl]furo[2,3-c]pyridine-2-carboxamide 413

N-[[(2S)-6-(3-methylbutanoyl)- 6-azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2- carboxamide 414

N-[[(2R)-6-(3-methylbutanoyl)- 6-azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2- carboxamide 415

N-[[6-(4-methyloxazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide 416

isopropyl 2-[(furo[2,3-c]pyridine-2- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate 417

(3-methyloxetan-3-yl) 2- [(furo[2,3-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate 418

N-[(6-benzoyl-6- azaspiro[2.5]octan-2- yl)methyl]-1,3-dihydropyrrolo[3,4-c]pyridine- 2-carboxamide 419

(3-methyloxetan-3-yl) (2S)-2-[(1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate

or a pharmaceutically acceptable salt thereof, or a stereoisomer or apharmaceutically acceptable salt of said stereoisomer.

Pharmaceutical Description

The dosage forms of the present invention may contain a mixture of oneor more compounds of this invention, and may include additionalmaterials known to those skilled in the art as pharmaceuticalexcipients. “Excipient” includes any excipient commonly used inpharmaceutics and should be selected on the basis of compatibility andthe release profile properties of the desired dosage form. Exemplaryexcipients include, e.g., binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, diluents, and the like. Exemplary excipientsinclude, e.g., acacia, gelatin, colloidal silicon dioxide, calciumglycerophosphate, calcium lactate, maltodextrin, glycerine, magnesiumsilicate, sodium caseinate, soy lecithin, sodium chloride, tricalciumphosphate, dipotassium phosphate, sodium stearoyl lactylate,carrageenan, monoglyceride, diglyceride, pregelatinized starch, and thelike. See, e.g., Hoover, John E., Remington's Pharmaceutical Sciences,Mack Publishing Co., Easton, Pa. 1975.

Exemplary excipients include: stabilizing additives such as gum acacia,gelatin, methyl cellulose, polyethylene glycol, carboxylic acids andsalts thereof, and polylysine; acidifying agents (acetic acid, glacialacetic acid, citric acid, fumaric acid, hydrochloric acid, dilutedhydrochloric acid, malic acid, nitric acid, phosphoric acid, dilutedphosphoric acid, sulfuric acid, tartaric acid); aerosol propellants(butane, dichlorodifluoro-methane, dichlorotetrafluoroethane, isobutane,propane, trichloromonofluoromethane); air displacements (carbon dioxide,nitrogen); alcohol denaturants (denatonium benzoate, methyl isobutylketone, sucrose octacetate); alkalizing agents (strong ammonia solution,ammonium carbonate, diethanolamine, diisopropanolamine, potassiumhydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodiumhydroxide, trolamine); anticaking agents (see “glidant” below);antifoaming agents (dimethicone, simethicone); antimicrobialpreservatives (benzalkonium chloride, benzalkonium chloride solution,benzelthonium chloride, benzoic acid, benzyl alcohol, butylparaben,cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol,dehydroacetic acid, ethylparaben, methylparaben, methylparaben sodium,phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuricnitrate, potassium benzoate, potassium sorbate, propylparaben,propylparaben sodium, sodium benzoate, sodium dehydroacetate, sodiumpropionate, sorbic acid, thimerosal, thymol); antioxidants (ascorbicacid, acorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate,sodium formaldehyde sulfoxylate, sodium metabisulfite, sodiumthiosulfate, sulfur dioxide, tocopherol, tocopherols excipient);buffering agents (acetic acid, ammonium carbonate, ammonium phosphate,boric acid, citric acid, lactic acid, phosphoric acid, potassiumcitrate, potassium metaphosphate, potassium phosphate monobasic, sodiumacetate, sodium citrate, sodium lactate solution, dibasic sodiumphosphate, monobasic sodium phosphate); capsule lubricants (see “tabletand capsule lubricant” below); chelating agents (edetate disodium,ethylenediaminetetraacetic acid and salts, edetic acid); coating agents(sodium carboxymethylcellulose, cellulose acetate, cellulose acetatephthalate, ethylcellulose, gelatin, pharmaceutical glaze, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, methacrylic acid copolymer, methylcellulose, polyethyleneglycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide,carnauba wax, microcrystalline wax, zein); colorants (caramel, red,yellow, black or blends, ferric oxide); complexing agents(ethylenediaminetetraacetic acid and salts (EDTA), edetic acid, gentisicacid ethanolmaide, oxyquinoline sulfate); desiccants (calcium chloride,calcium sulfate, silicon dioxide); emulsifying and/or solubilizingagents (acacia, cholesterol, diethanolamine (adjunct), glycerylmonostearate, lanolin alcohols, lecithin, mono- and di-glycerides,monoethanolamine (adjunct), oleic acid (adjunct), oleyl alcohol(stabilizer), poloxamer, polyoxyethylene 50 stearate, polyoxyl 35 casteroil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether,polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20,polysorbate 40, polysorbate 60, polysorbate 80, propylene glycoldiacetate, propylene glycol monostearate, sodium lauryl sulfate, sodiumstearate, sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate, sorbitan monostearate, stearic acid, trolamine,emulsifying wax); filtering aids (powdered cellulose, purified siliceousearth); flavors and perfumes (anethole, benzaldehyde, ethyl vanillin,menthol, methyl salicylate, monosodium glutamate, orange flower oil,peppermint, peppermint oil, peppermint spirit, rose oil, stronger rosewater, thymol, tolu balsam tincture, vanilla, vanilla tincture,vanillin); glidants and/or anticaking agents (calcium silicate,magnesium silicate, colloidal silicon dioxide, talc); humectants(glycerin, hexylene glycol, propylene glycol, sorbitol); plasticizers(castor oil, diacetylated monoglycerides, diethyl phthalate, glycerin,mono- and di-acetylated monoglycerides, polyethylene glycol, propyleneglycol, triacetin, triethyl citrate); polymers (e.g., cellulose acetate,alkyl celloloses, hydroxyalkylcelloloses, acrylic polymers andcopolymers); solvents (acetone, alcohol, diluted alcohol, amylenehydrate, benzyl benzoate, butyl alcohol, carbon tetrachloride,chloroform, corn oil, cottonseed oil, ethyl acetate, glycerin, hexyleneglycol, isopropyl alcohol, methyl alcohol, methylene chloride, methylisobutyl ketone, mineral oil, peanut oil, polyethylene glycol, propylenecarbonate, propylene glycol, sesame oil, water for injection, sterilewater for injection, sterile water for irrigation, purified water);sorbents (powdered cellulose, charcoal, purified siliceous earth);carbon dioxide sorbents (barium hydroxide lime, soda lime): stiffeningagents (hydrogenated castor oil, cetostearyl alcohol, cetyl alcohol,cetyl esters wax, hard fat, paraffin, polyethylene excipient, stearylalcohol, emulsifying wax, white wax, yellow wax); suspending and/orviscosity-increasing agents (acacia, agar, alginic acid, aluminummonostearate, bentonite, purified bentonite, magma bentonite, carbomer934p, carboxymethylcellulose calcium, carboxymethylcellulose sodium,carboxymethylcellulose sodium 12, carrageenan, microcrystalline andcarboxymethylcellulose sodium cellulose, dextrin, gelatin, guar gum,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, magnesium aluminum silicate, methylcellulose, pectin,polyethylene oxide, polyvinyl alcohol, povidone, propylene glycolalginate, silicon dioxide, colloidal silicon dioxide, sodium alginate,tragacanth, xanthan gum): sweetening agents (aspartame, dextrates,dextrose, excipient dextrose, fructose, mannitol, saccharin, calciumsaccharin, sodium saccharin, sorbitol, solution sorbitol, sucrose,compressible sugar, confectioner's sugar, syrup); tablet binders(acacia, alginic acid, sodium carboxymethylcellulose, microcrystallinecellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum,hydroxypropyl methylcellulose, methylcellulose, polyethylene oxide,povidone, pregelatinized starch, syrup); tablet and/or capsule diluents(calcium carbonate, dibasic calcium phosphate, tribasic calciumphosphate, calcium sulfate, microcrystalline cellulose, powderedcellulose, dextrates, dextrin, dextrose excipient, fructose, kaolin,lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose,compressible sugar, confectioner's sugar): tablet disintegrants (alginicacid, microcrystalline cellulose, croscarmellose sodium, corspovidone,polacrilin potassium, sodium starch glycolate, starch, pregelatinizedstarch); tablet and/or capsule lubricants (calcium stearate, glycerylbehenate, magnesium stearate, light mineral oil, polyethylene glycol,sodium stearyl fumarate, stearic acid, purified stearic acid, talc,hydrogenated vegetable oil, zinc stearate); tonicity agent (dextrose,glycerin, mannitol, potassium chloride, sodium chloride); vehicle:flavored and/or sweetened (aromatic elixir, compound benzaldehydeelixir, iso-alcoholic elixir, peppermint water, sorbitol solution,syrup, tolu balsam syrup); vehicle: oleaginous (almond oil, corn oil,cottonseed oil, ethyl oleate, isopropyl myristate, isopropyl palmitate,mineral oil, light mineral oil, myristyl alcohol, octyldodecanol, oliveoil, peanut oil, persic oil, sesame oil, soybean oil, squalane);vehicle: solid carrier (sugar spheres); vehicle; sterile (bacteriostaticwater for injection, bacteriostatic sodium chloride injection);viscosity-increasing (see “suspending agent” below); water repellingagent (cyclomethicone, dimethicone, simethicone); and wetting and/orsolubilizing agent (benzalkonium chloride, benzethonium chloride,cetylpyridinium chloride, docusate sodium, nonoxynol 9, nonoxynol 10,octoxynol 9, poloxamer, polyoxyl 35 castor oil, polyoxyl 40,hydrogenated castor oil, polyoxyl 50 stearate, polyoxyl 10 oleyl ether,polyoxyl 20, cetostearyl ether, polyoxyl 40 stearate, polysorbate 20,polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate,sorbitan monolaureate, sorbitan monooleate, sorbitan monopalmitate,sorbitan monostearate, tyloxapol). This list is not meant to beexclusive, but instead merely representative of the classes ofexcipients and the particular excipients which may be used in dosageforms of the present invention.

In certain aspects, the invention relates to methods of treatingdiseases or conditions mediated by elevated levels of NAMPT, or whichare generally mediated by NAMPT activity. Such disease or condition canbe one or more selected from the group consisting of cancer, ovariancancer, breast cancer, uterine cancer, colon cancer, cervical cancer,lung cancer, prostate cancer, skin cancer, bladder cancer, pancreaticcancer, leukemia, lymphoma, Hodgkin's disease, viral infections, HumanImmunodeficiency Virus, hepatitis virus, herpes virus, herpes simplex,inflammatory disorders, irritable bowel syndrome, inflammatory boweldisease, rheumatoid arthritis, asthma, chronic obstructive pulmonarydisease, osteoarthritis, osteoporosis, dermatitis, atoptic dermatitis,psoriasis, systemic lupus erythematosis, multiple sclerosis, psoriaticarthritis, ankylosing spodylitis, graft-versus-host disease, Alzheimer'sdisease, cerebrovascular accident, atherosclerosis, diabetes,glomerulonephiritis, metabolic syndrome, non-small cell lung cancer,small cell lung cancer, multiple myeloma, leukemias, lymphomas, squamouscell cancers, kidney cancer, uretral and bladder cancers, cancers ofhead and neck, and cancers of the brain and central nervous system(CNS).

The inventive compounds can be useful in the therapy of proliferativediseases such as, but not limited to cancer, autoimmune diseases, viraldiseases, fungal diseases, neurological/neurodegenerative disorders,arthritis, inflammation, anti-proliferative (e.g., ocular retinopathy),neuronal, alopecia and cardiovascular disease.

More specifically, the compounds can be useful in the treatment of avariety of cancers, including (but not limited to) the following:carcinoma, including that of the bladder, breast, colon, kidney, liver,lung, including small cell lung cancer, non-small cell lung cancer, headand neck, esophagus, gall bladder, ovary, pancreas, stomach, cervix,thyroid, prostate, and skin, including squamous cell carcinoma,hematopoietic tumors of lymphoid lineage, including leukemia, acutelymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma,T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy celllymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma,hematopoietic tumors of myeloid lineage, including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia, tumors of mesenchymal origin, including fibrosarcoma andrhabdomyosarcoma, tumors of the central and peripheral nervous system,including astrocytoma, neuroblastoma, glioma and schwannomas, and othertumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma,xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer andKaposi's sarcoma.

The compounds of the invention may induce or inhibit apoptosis.

The compounds of the invention may also be useful in the chemopreventionof cancer. Chemoprevention is defined as inhibiting the development ofinvasive cancer by either blocking the initiating mutagenic event or byblocking the progression of pre-malignant cells that have alreadysuffered an insult or inhibiting tumor relapse.

A further aspect of the invention is a method of inhibiting a NAMPTpathway in a subject, said method comprising administering to saidsubject a pharmaceutically acceptable amount of a compound of theinvention to a subject in need thereof.

Another embodiment of the invention comprises a pharmaceuticalformulation of the invention, wherein the pharmaceutical formulation,upon administration to a human, results in a decrease in tumor burden.

Still another embodiment of the invention is a pharmaceuticalformulation comprising at least one compound of Formula I and apharmaceutically acceptable excipient. Such formulations may furthercomprise one or more adjunctive active agent. The pharmaceuticalformulations of the invention may further comprise a therapeuticeffective amount of an adjunctive active agent.

The compounds of the present invention are also useful in combinationtherapies with at least one adjunctive active agent. Such methodsinclude regimes in which the compound of the invention and the at leastone adjunctive active agent are administered simultaneously orsequentially. Also useful are pharmaceutical compositions in which atleast one compound of the present invention and at least one adjunctiveactive agent are combined in a single formulation.

The expression “adjunctive active agent” generally refers to agentswhich targets the same or a different disease, symptom, or medicalcondition as the primary therapeutic agent. Adjunctive active agents maytreat, alleviate, relieve, or ameliorate side effects caused byadministration of the primary therapeutic agents. Examples of adjunctiveactive agents include, but are not limited to, antineoplastic agents,filgrastim, and erythropoietin. Such agents include those which modifyblood cell growth and maturation. Non-limiting examples of adjunctiveactive agent are filgrastim, pegfilgrastim and erythropoietin. Othersuch adjunctive active agents include those which inhibit nauseaassociated with administration of chemotherapeutic agents, such as a5-HT₃ receptor inhibitor (e.g., dolansetron, granisetron, orondansetron), with or without dexamethasone. The invention alsodescribes one or more uses of the compounds of the present inventionwith an adjunctive active agent such as TNF, GCSF, or otherchemotherapeutic agents. Additional adjunctive active agents includethose that mediate cytotoxicity of NAMPT inhibitors, such as nicotinicacid rescue agents, or other compounds that play a role in the NAMPTpathway, such as niacin (nicotinic acid), nicotinamide, or relatedcompounds, or modified release formulations of such compounds, forexample, NIASPAN®.

The terms “chemotherapeutic agent” and “antineoplastic agent” generallyrefer to agents, which treat, prevent, cure, heal, alleviate, relieve,alter, remedy, ameliorate, improve, or affect malignancies and theirmetastasis. Examples of such agents include, but are not limited to,prednisone, fluorouracil (e.g., 5-fluorouracil (5-FU)), anastrozole,bicalutamide, carboplatin, cisplatin, chlorambucil, cisplatin,carboplatin, docetaxel, doxorubicin, flutamide, interferon-alpha,letrozole, leuprolide, megestrol, mitomycin, oxaliplatin, paclitaxel,plicamycin (Mithracin™), tamoxifen, thiotepa, topotecan, valrubicin,vinblastine, vincristine, and any combination of any of the foregoing.

The invention is also directed to a method of treating or preventing adisorder associated with excessive rate of growth of cells in a mammalcomprising administering to the mammal an effective amount of thepharmaceutical formulation of the invention. Non-limiting examples ofdisorder include cancer or metastasis from malignant tumors.

Another aspect of the invention is a method of inhibiting tumor cellgrowth and rate of division in a mammal with cancer, or other disorderassociated with abnormally dividing cells comprising administering tothe mammal an effective amount of the pharmaceutical formulation of thisinvention.

Another embodiment of the invention is a method of treating bone paindue to excessive growth of a tumor or metastasis to bone in a mammal inneed thereof comprising administering to the mammal an effective amountof the pharmaceutical formulation of this invention.

A further embodiment of the invention is a method of preparing apharmaceutical formulation comprising mixing at least one compound ofthe present invention, and, optionally, one or more pharmaceuticallyacceptable excipients.

The invention is also directed to methods of synthesizing compounds ofthe present invention.

Still another aspect of this invention is to provide a method fortreating, preventing, inhibiting or eliminating a disease or conditionin a patient by inhibiting NAMPT in said patient by administering atherapeutically effective amount of at least one compound of thisdisclosure, wherein said disease or condition is selected from the groupconsisting of cancer, ovarian cancer, breast cancer, uterine cancer,colon cancer, cervical cancer, lung cancer, prostate cancer, skincancer, bladder cancer, pancreatic cancer, leukemia, lymphoma, Hodgkin'sdisease, viral infections, Human Immunodeficiency Virus, hepatitisvirus, herpes virus, herpes simplex, inflammatory disorders, irritablebowel syndrome, inflammatory bowel disease, rheumatoid arthritis,asthma, chronic obstructive pulmonary disease, osteoarthritis,osteoporosis, dermatitis, atoptic dermatitis, psoriasis, systemic lupuserythematosis, multiple sclerosis, psoriatic arthritis, ankylosingspodylitis, graft-versus-host disease, Alzheimer's disease,cerebrovascular accident, atherosclerosis, diabetes,glomerulonephiritis, metabolic syndrome, non-small cell lung cancer,small cell lung cancer, multiple myeloma, leukemias, lymphomas, squamouscell cancers, kidney cancer, uretral and bladder cancers, cancers ofhead and neck, cancers of the brain and central nervous system.

In a certain embodiment, the compounds of Formula I can be used in thetreatment of solid and liquid tumors, non-small cell lung cancer,leukemia, lymphoma, ovarian cancer, glioma, breast cancer, uterinecancer, colon cancer, cervical cancer, lung cancer, prostate cancer,skin cancer, rhino-gastric tumors, colorectal cancer, CNS cancer,bladder cancer, pancreatic cancer and Hodgkin's disease.

In a certain embodiment, the compounds of Formula I can be used in thetreatment of solid and liquid tumors, non-small cell lung cancer,leukemia, lymphoma, ovarian cancer, breast cancer, uterine cancer, coloncancer, cervical cancer, lung cancer, prostate cancer, skin cancer,rhino-gastric tumors, colorectal cancer, bladder cancer, pancreaticcancer and Hodgkin's disease.

Another embodiment is a pharmaceutical formulation comprising apharmaceutically acceptable compound of the present invention, whichprovides, upon administration to a subject (e.g., a human), a decreasein tumor burden and/or metastases. The pharmaceutical formulation can beadministered by oral means or other suitable means.

Yet another embodiment is a method of treating ovarian cancer in asubject (e.g., a human) in need thereof by administering to the subjectan effective amount of the compound or the pharmaceutical formulation ofthe present invention.

Yet another embodiment is a method of treating non-small cell lungcancer (NSCLC) in a subject (e.g., a human) in need thereof byadministering to the subject an effective amount of the compound or thepharmaceutical formulation of the present invention.

Yet another embodiment is a method of treating colon cancer in a subject(e.g., a human) in need thereof by administering to the subject aneffective amount of the compound or the pharmaceutical formulation ofthe present invention.

Yet another embodiment is a method of treating breast cancer in asubject (e.g., a human) in need thereof by administering to the subjectan effective amount of the pharmaceutical formulation of the presentinvention.

Yet another embodiment is a method of treating leukemia in a subject(e.g., a human) in need thereof by administering to the subject aneffective amount of the compound or the pharmaceutical formulation ofthe present invention.

Yet another embodiment is a method of treating colon cancer before orafter surgical resection and/or radiation therapy, in a subject (e.g., ahuman) in need thereof by administering to the subject an effectiveamount of the compound or the pharmaceutical formulation of the presentinvention.

Yet another embodiment is a method of treating cancer before or aftersurgical resection and/or radiation therapy, in a subject (e.g., ahuman) in need thereof by administering to the subject an effectiveamount of the compound or the pharmaceutical formulation of the presentinvention, including adjunctive therapy to treat nausea, with or withoutdexamethasone.

Yet another embodiment is a method of treating cancer before or aftersurgical resection and or radiation therapy, in a subject (c g., ahuman) in need thereof by administering to the subject an effectiveamount of the compound or the pharmaceutical formulation of the presentinvention, including adjunctive therapy with one or more additionaltherapeutic agents, or their pharmaceutically acceptable salts.Non-limiting examples of such additional therapeutic agents includecytotoxic agents (such as for example, but not limited to, DNAinteractive agents (such as cisplatin or doxorubicin)); taxanes (e.g.taxotere, taxol); topoisomerase II inhibitors (such as etoposide);topoisomerase I inhibitors (such as irinotecan (or CPT-11), camptostar,or topotecan); tubulin interacting agents (such as paclitaxel, docetaxelor the epothilones); hormonal agents (such as tamoxifen); thymidilatesynthase inhibitors (such as 5-fluorouracil or 5-FU); anti-metabolites(such as methoxtrexate); alkylating agents (such as temozolomide,cyclophosphamide); Farnesyl protein transferase inhibitors (such as,SARASAR™.(4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,-6]cyclohepta[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoethyl]-1-piperidine-carboxamide,or SCH 66336), tipifarnib (Zamestra® or R115777 from JanssenPharmaceuticals), L778,123 (a farnesyl protein transferase inhibitorfrom Merck & Company, Whitehouse Station, N.J.), BMS 214662 (a farnesylprotein transferase inhibitor from Bristol-Myers Squibb Pharmaceuticals,Princeton, N.J.); signal transduction inhibitors (such as, Iressa® (fromAstra Zeneca Pharmaceuticals, England), Tarceva® (EGFR kinaseinhibitors), antibodies to EGFR (e.g., C225), GLEEVEC® (C-abl kinaseinhibitor from Novartis Pharmaceuticals, East Hanover, N.J.);interferons such as, for example, Intron® (from Merck & Company),Peg-Intron® (from Merck & Company); hormonal therapy combinations;aromatase combinations; ara-C, adriamycin, cytoxan, and gemcitabine.

Other anti-cancer (also known as anti-neoplastic) agents include but arenot limited to Uracil mustard, Chlormethine, Ifosfamide, Melphalan,Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,oxaliplatin (ELOXATIN® from Sanofi-Synthelabo Pharmaceuticals, France),Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade®, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,Ifosfomide, Rituximab, C225, and Campath, 5-fluorouracil and leucovorin,with or without a 5-HT₃ receptor inhibitor (e.g., dolansetron,granisetron, ondansetron) with or without dexamethasone.

Additionally, according to the present invention, the compounds of theinvention described herein may be administered and/or formulated incombination with an adjunctive active agent. In certain embodiments, theadjunctive active agent is niacin, nicotinamide, nicotinic acid,nicotinamide mononucleotide (NMN), or variations thereof, includingmodified release formulations of niacin, such as NIASPAN®. Niacin,nicotinamide, nicotinic acid, nicotinamide mononucleotide (NMN), orvariations thereof have also been described in the literature as “rescueagents” or “rescuing agents” and these terms have been used herein. Therole of nicotinamide and/or nicotinic acid as a rescuing or rescue agenthas for example been described by Beauparlant et al. in Anti-CancerDrugs 2009, 20:346-354 and by Rongvaux et al. in The Journal ofImmunology, 2008, 181: 4685-4695. These two references describe the roleof a rescuing or rescue agent with regards to ameliorating possibletoxic effects of NAMPT inhibitors.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein (oras known to those skilled in the art) and the other pharmaceuticallyactive agents or treatments within its dosage range. For example, theCDC2 inhibitor olomucine has been found to act synergistically withknown cytotoxic agents in inducing apoptosis (J. Cell Sci., (1995) 108,2897). The compounds of the invention may also be administeredsequentially with known anticancer or cytotoxic agents when acombination formulation is inappropriate. In any combination treatment,the invention is not limited in the sequence of administration;compounds of the disclosed Formulas may be administered either prior toor after administration of the known anticancer or cytotoxic agent. Forexample, the cytotoxic activity of the cyclin-dependent kinase inhibitorflavopiridol is affected by the sequence of administration withanticancer agents. Cancer Research, (1997) 57, 3375. Such techniques arewithin the skills of persons skilled in the art as well as attendingphysicians.

Any of the aforementioned methods may be augmented by administration offluids (such as water), loop diuretics, one or more adjunctive activeagents, such as a chemotherapeutic or antineoplastic agent, such asleucovorin and fluorouracil, or an adjunctive chemotherapeutic agent(such as filgrastim and erythropoietin), or any combination of theforegoing.

Yet another embodiment is a method for administering a compound of theinstant invention to a subject (e.g., a human) in need thereof byadministering to the subject the pharmaceutical formulation of thepresent invention.

Yet another embodiment is a method of preparing a pharmaceuticalformulation of the present invention by mixing at least onepharmaceutically acceptable compound of the present invention, and,optionally, one or more pharmaceutically acceptable additives orexcipients.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18th Edition, (1990), Mack Publishing Co., Easton, Pa.

The compositions and formulations of the invention can be administeredas sterile compositions and sterile formulations. Sterile pharmaceuticalformulations are compounded or manufactured according topharmaceutical-grade sterilization standards (e.g., United StatesPharmacopeia Chapters 797, 1072, and 1211; California Business &Professions Code 4127.7; 16 California Code of Regulations 1751, 21 Codeof Federal Regulations 21, or ex-U.S. counterparts to such regulations)known to those of skill in the art.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

The compound can be administered orally or intravenously.

The pharmaceutical preparation can be in a unit dosage form. In suchform, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 1000 mg, for example fromabout 1 mg to about 500 mg, in particular from about 1 mg to about 250mg, or from about 1 mg to about 25 mg, according to the particularapplication.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two tofour divided doses.

Schemes and Examples

Exemplary, non-limiting, chemical entities and methods useful inpreparing compounds of the invention will now be described by referenceto illustrative synthetic schemes for their general preparation belowand the specific examples that follow. Those skilled in the art willappreciate that other synthetic routes may be used to synthesize thecompounds according to the invention. Although specific startingmaterials and reagents are depicted and discussed herein, other startingmaterials and reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of theexemplary compounds prepared by the described methods can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Each of the reactions depicted in the reactionschemes is preferably run at a temperature from about 0° C. to thereflux temperature of the solvent used. Unless otherwise specified, thevariables shown in the schemes below are as defined above in referenceto Formula I.

Compounds according to the invention may be synthesized by syntheticroutes that include processes analogous to those well-known in thechemical arts, particularly in light of the description containedherein, and those for other heterocycles described in: ComprehensiveHeterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997,e.g. Volume 3; Liebigs Annalen der Chemie, (9):1910-16, (1985);Helvetica Chimica Acta, 41:1052-60, (1958); Arzneimittel-Forschung,40(12). 1328-31, (1990), each of which are expressly incorporated byreference. Starting materials are generally available from commercialsources such as Sigma-Aldrich Chemicals (Milwaukee, Wis.) or are readilyprepared using methods well known to those skilled in the art (e.g.,prepared by methods generally described in Louis F. Fieser and MaryFieser, Reagents for Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed.Springer-Verlag, Berlin, including supplements (also available via theBeilstein online database).

Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing compounds accordingto the invention and necessary reagents and intermediates are known inthe art and include, for example, those described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia ofReagents for Organic Synthesis, John Wiley and Sons (1995) andsubsequent editions thereof. The need for such protection will varydepending on the nature of the remote functionality and the conditionsof the preparation methods. Suitable amino-protecting groups includeacetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz)and 9-fluorenylmethyleneoxycarbonyl (Fmoc) The need for such protectionis readily determined by one skilled in the art.

Additional particularly useful reactions in preparing compounds of thepresent invention include alkylation, reductive amination, oxidation,reduction, and hydrolysis reactions. Such transformations are wellwithin the ordinary skill in the art.

Compounds according to the invention may be prepared singly or ascompound libraries comprising, for example, at least two, or 5 to 1,000compounds, or 10 to 100 compounds. Libraries of compounds of Formula Imay be prepared by a combinatorial “split and mix” approach or bymultiple parallel syntheses using either solution phase or solid phasechemistry, by procedures known to those skilled in the art. Thus,according to a further aspect of the invention there is provided acompound library comprising at least two compounds of Formula I, orpharmaceutically acceptable salts thereof.

In the methods of preparing compounds according to the invention, it maybe advantageous to separate reaction products from one another and/orfrom starting materials. The desired products of each step or series ofsteps is separated and/or purified to the desired degree of homogeneityby the techniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; size exclusion; ion exchange; high, medium and lowpressure liquid chromatography methods and apparatus; small scaleanalytical; simulated moving bed (SMB) and preparative thin or thicklayer chromatography, as well as techniques of small scale thin layerand flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like. Selection of appropriate methodsof separation depends on the nature of the materials involved, such as,boiling point and molecular weight in distillation and sublimation,presence or absence of polar functional groups in chromatography,stability of materials in acidic and basic media in multiphaseextraction, and the like.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S. “Stereochemistry of OrganicCompounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,(1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: “DrugStereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, a-methyl-b-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,a-methoxy-a-(trifluoromethyl)phenyl acetate of the racemic mixture andanalyzing the 1H NMR spectrum for the presence of the two atropisomericenantiomers or diastereomers (Jacob III. J. Org. Chem. (1982) 47:4165).Stable diastereomers of atropisomeric compounds can be separated andisolated by normal- and reverse-phase chromatography following methodsfor separation of atropisomeric naphthyl-isoquinolines (WO 96/15111). Bymethod (3), a racemic mixture of two enantiomers can be separated bychromatography using a chiral stationary phase (“Chiral LiquidChromatography” (1989) W. J. Lough, Ed., Chapman and Hall, New York;Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or purifiedenantiomers can be distinguished by methods used to distinguish otherchiral molecules with asymmetric carbon atoms, such as optical rotationand circular dichroism.

Abbreviations and acronyms used in the following Schemes and elsewhereherein are defined as follows:

-   -   CDCl₃ deuterated chloroform    -   CD₃OD deuterated methanol    -   δ chemical shift (ppm)    -   DCM Dichloromethane    -   DIPEA Diisopropylethylamine    -   DMF N,N-dimethylformamide    -   DMSO Dimethyl sulfoxide    -   EDCI 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide    -   ELSD Evaporative light scattering detector    -   equiv Molar equivalent    -   ESI Electrospray ionization    -   h Hour(s)    -   H₂ Hydrogen gas    -   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate    -   ¹H NMR proton nuclear magnetic resonance spectroscopy    -   HOBt 1-Hydroxybenzotriazole    -   HPLC High performance liquid chromatography    -   LC/MS Liquid chromatography-mass spectrometry    -   MeOH Methanol    -   MHz megahertz    -   min Minute(s)    -   PDA Photo diode array detector    -   psi Pounds per square inch    -   rt Room temperature    -   Raney-Ni Raney Nickel    -   R_(f) Retention factor    -   TFA Trifluoroacetic acid    -   Tf₂O Trifluoromethanesulfonic anhydride    -   THF Tetrahydrofuran    -   TLC Thin layer chromatography

Exemplary general reaction schemes that are useful in preparingcompounds of the invention are described below.

Compounds of Formula I may be prepared as shown above in Scheme A.Compounds of Formula A, in which X is, for example, OH, chloro, orbromo, are reacted with amines B to produce compounds of Formula I.Where X is OH, coupling reactions may occur in the presence of acoupling reagent such as EDCI, HATU, or HOBt, and a base (e.g., K₂CO₃,Cs₂CO₃, trialkylamine, sodium or potassium alkoxide) in an inert solventsuch as dichloromethane, N,N-dialkylformamide, N,N-dialkylacetamide,dialkylethers, cyclic ethers, DMSO, or N-methyl-2-pyrrolidinone, or amixture thereof, at temperatures ranging from −78° C. to 200° C. Suchcoupling reactions between amines and acids are well-known in the art.Alternatively, compounds A where X is bromo or chloro may be reactedwith amines B in the presence of a suitable base, such as triethylamine,K₂CO₃, or Cs₂CO₃, to form compounds of Formula I.

Certain compounds of Formula I, wherein the R group is connected to thecarbonyl carbon via a nitrogen atom within the R group (forming a urea)may be prepared according to General Scheme B. Amines B are activatedusing methods known to one of skill in the art, wherein LG is a suitableleaving group such as an alkoxy or halo group, and the activatedcompounds C are then reacted, either in situ or in a separate reactionstep, with a suitably substituted amine R²⁰R²¹NH in the presence of abase such as a trialkylamine, to form compounds of Formula I.

Amines B may be prepared according to General Scheme C. The spirocyclicnitrogen in amines D, where PG₁ and PG₂ are suitable nitrogen protectinggroups, such as a Boc or CBz group, or PG₁ is R—C(O)— (in which casecompounds D may be formed as shown in Scheme A), is deprotected usingstandard protecting group chemistry to form amines E. Acylation orsulfonylation with suitably substituted acid chlorides or sulfonylchlorides, in the of a base such as a tertiary amine base, or withsuitably substituted acids R^(a)CO₂H under peptide coupling conditionsas described in Scheme A, generate compounds F. Where PG₁ is aprotecting group, removal of that group generates amines B.

Those having skill in the art will recognize that the startingmaterials, reagents, and conditions described in the above generalschemes may be varied and additional steps employed to produce compoundsencompassed by the present inventions. Additionally, one of skill in theart will recognize that the reaction steps presented in the aboveSchemes may be performed in a different order.

Methods of Chemical Analysis of Example Compounds

Unless otherwise indicated, ¹H NMR spectra were recorded at ambienttemperature using one of the following machines: Varian Unity Inova (400MHz) spectrometer with a triple resonance 5 mm probe, Bruker AvanceDRX400 (400 MHz) spectrometer with a triple resonance 5 mm probe, aBruker Avance DPX 300 (300 MHz) equipped with a standard 5 mm dualfrequency probe for detection of ¹H and ¹³C, a Bruker AVIII (400 MHz)using a BBI Broad Band Inverse 5 mm probe, or a Bruker AVIII (500 MHz)using a QNP (Quad Nucleus detect) 5 mm probe. Chemical shifts areexpressed in ppm relative to an internal standard; tetramethylsilane(ppm=0.00). The following abbreviations have been used: br=broad signal,s=singlet, d=doublet, dd=double doublet, t=triplet, q=quartet,m=multiplet.

High Performance Liquid Chromatography-Mass Spectrometry (LC/MS) andsupercritical fluid chromatography (SFC) experiments to determineretention times (RT) and associated mass ions, e.g., [M+H]⁻, [M+Na]⁺,[M−H]⁻, were performed using one of the following methods:

Method A Instrument: SHIMADZU LCMS-2010EV

LC Parameters: Column: Shim-pack XR-ODS, 2.2 um, 3.0*50 mm; Mobile PhaseA: Water/0.05% TFA; Mobile Phase B: Acetonitrile; Gradient: 5% to 100% Bin 2.0 min, 100% B for 1.1 min, 100% to 5% B in 0.2 min, then stop; FlowRate: 1.0 mL/min; Column Temperature: 40° C.; Detector: 254 nm and ELSD;Sample Preparation: 1 mg/mL in Methanol; Injection Volume: 1 μL.MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.5 kv;Heat Block: 250° C.; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900(m/z); Detector voltage: 1.7 kv.

Method B Instrument: SHIMADZU LCMS-2010EV

LC Parameters: Column: Waters XBridge C18, 3.0×50 mm, 3.5μ; Mobile PhaseA: Water/5 mM Ammonium Acetate; Mobile Phase B: Methanol; Gradient: 10%to 100% B in 1.8 min, 100% B for 1.3 min, 100% to 10% B in 0.1 min, thenstop; Flow Rate: 0.9 mL/min; Column Temperature: 40° C.; Detector: PDAand ELSD; Sample Preparation: 1 mg/mL in Methanol; Injection Volume: 1μL.MS Parameters: Interface: ESI (Positive & Negative); Interface Voltage:4.0 kv; Heat Block: 250° C.; Nebulizing Gas: 1.50 L/min; Scan Range:90-900 (m/z); Detector voltage: 1.5 kv.

Method C Instrument: SHIMADZU LCMS-2010EV

LC Parameters: Column: Shim-pack XR-ODS, 2.2 um, 3.0*50 mm; Mobile PhaseA: Water/0.05% TFA; Mobile Phase B: Acetonitrile/0.05% TFA; Gradient: 5%to 100% B in 2.0 min, 100% B for 1.1 min, 100% to 5% B in 0.2 min, thenstop; Flow Rate: 1.0 mL/min; Column Temperature: 40° C.; Detector: 254nm and ELSD; Sample Preparation: 1 mg/mL in Methanol; Injection Volume:1 μL.MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.5 kv;Heat Block: 250° C.; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900(m/z); Detector voltage: 1.5 kv.

Method D Instrument: SHIMADZU LC/MS-2010EV

LC Parameters: Column: Waters Xselect C18, 3.0×50 mm, 3.5 μm; MobilePhase A: Water/0.1% formic acid; Mobile Phase B: Acetonitrile/0.05%formic acid; Gradient: 5% to 100% B in 2.0 min, 100% B for 1.2 min, 100%to 5% B in 0.1 min, then stop; Flow Rate: 0.9 mL/min; ColumnTemperature: 35° C.; Detector: 254 nm and ELSD; Sample Preparation: 1mg/mL in Methanol; Injection Volume: 1 μL.MS Parameters: Interface: ESI (Positive & Negative); Interface Voltage:4.5 kv; Heat Block: 250° C.; Nebulizing Gas: 1.50 L/min; Scan Range:90-900 (m/z); Detector voltage: 1.5 kv.

Method E Instrument: SHIMADZU LCMS-2010EV

LC Parameters: Column: Shim-pack XR-ODS, 3.0×50 mm, 2.2 μm; Mobile PhaseA: Water/0.05% TFA; Mobile Phase B: Acetonitrile; Gradient: 5% to 100% Bin 2.0 min, 100% B for 1 min, 100% to 5% B in 0.3 min, then stop; FlowRate: 1.0 mL/min; Column Temperature: 40° C.; Detector: 254 nm and ELSD;Sample Preparation: 1 mg/mL in Methanol; Injection Volume: 1 μL.MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.5 kv;Heat Block: 250° C.; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900(m/z); Detector voltage: 1.3 kv.

Method F Instrument: SHIMADZU LCMS-2010EV

LC Parameters: Column: Shim-pack XR-ODS, 3.0×50 mm, 2.2 um; Mobile PhaseA: Water/0.05% TFA; Mobile Phase B: Acetonitrile; Gradient: 5% to 100% Bin 2.0 min, 100% B for 1.2 min, 100% to 5% B in 0.1 min, then stop; FlowRate: 1.0 mL/min; Column Temperature: 40° C.; Detector: 254 nm and ELSD;Sample Preparation: 1 mg/mL in Methanol; Injection Volume: 1 μL.MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.5 kv;Heat Block: 250° C.; Nebulizing Gas: 1.50 L/min; Scan Range: 70-900(m/z); Detector voltage: 1.1 kv.

Method G Instrument: SHIMADZU LC/MS-2020EV

LC Parameters: Column: Shim-pack XR-ODS, 50 mm*3.0 mm, 2.2 um; MobilePhase A: Water/0.05% TFA; Mobile Phase B: Acetonitrile; Gradient: 5% to100% B in 2.1 min, 100% B for 0.8 min, 100% to 5% B in 0.1 min, thenstop; Flow Rate: 1.0 mL/min; Column Temperature: 40° C.; Detector: 254nm and ELSD; Sample Preparation 1 mg/mL in Acetonitrile; InjectionVolume 1 μL.MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.5 kv;Heat Block: 250° C.; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900(m/z); Detector voltage: 1.05 kv.

Method H Instrument: SHIMADZU LCMS-2020

LC Parameters: Column: Shim-pack XR-ODS, 2.2 um, 3.0*50 mm; Mobile PhaseA: Water/0.05% TFA; Mobile Phase B: Acetonitrile/0.05% TFA; Gradient: 5%to 100% B in 2.0 min, 100% B for 1.2 min, 100% to 5% B in 0.1 min, thenstop, Flow Rate: 1.0 mL/min; Column Temperature: 40° C.; Detector: 254nm and ELSD; Sample Preparation: 1 mg/mL in Methanol, Injection Volume:1 μL.MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.5 kv;Heat Block: 250° C.; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900(m/z); Detector voltage: 1.1 kv.

Method I Instrument: SHIMADZU LCMS-2020

LC Parameters: Column: Shim-pack XR-ODS 50*3.0 nm, 2.2 um; Mobile PhaseA: Water/0.05% TFA; Mobile Phase B: Acetonitrile/0.05% TFA; Gradient: 5%B to 100% B for 2.0 min, 100% B for 1.2 min, 100% B to 5% in 0.1 min,then stop; Flow Rate: 1.0 mL/min; Column Temperature: 40° C.; Detector:254 nm and ELSD; Sample Preparation: 1 mg/mL in Methanol; InjectionVolume: 1 μL.MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.5 kv;Heat Block: 250° C.; Nebulizing Gas: 1.50 L/min; Scan Range: 70-900(m/z); Detector voltage: 1.05 kv.

Method J Instrument: SHIMADZU LCMS-2020

LC Parameters: Column: Shim-pack XR-ODS, 3.0×50 mm, 2.2μ; Mobile PhaseA: Water/0.05% TFA; Mobile Phase B: Acetonitrile; Gradient: 5% to 100% Bin 2.0 min, 100% B for 1.2 min, 100% to 5% B in 0.2 min, then stop; FlowRate: 1.0 mL/min; Column Temperature: 40° C.; Detector: 254 nm and ELSD;Sample Preparation: 1 mg/mL in Acetonitrile; Injection Volume: 1 μL.MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.5 kv;Heat Block; 200° C.; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900(m/z); Detector voltage: 1.05 kv.

Method K Instrument: SHIMADZU LCMS-2020

LC Parameters: Column: Gemini-NX 3u C18 110A; Mobile Phase A:Water/0.04% Ammonia; Mobile Phase B: Acetonitrile; Gradient: 5% to 100%B in 2.0 min, 100% B for 1.1 min, 100% to 5% B in 0.1 min, then stop;Flow Rate: 1.0 mL/min; Column Temperature: 35° C.; Detector: 254 nm andELSD; Sample Preparation: 1 mg/mL in Methanol; Injection Volume: 1 μL.MS Parameters: Interface: ESI (Positive & Negative); Interface Voltage:4.5 kv; Heat Block: 200° C.; Nebulizing Gas: 1.50 L/min; Scan Range:90-900 (m/z); Detector voltage: 0.75 kv.

Method L

Instrument Waters mass-directed Mobile phase A 0.1% H₂O w/NH₄OH Mobilephase B acetonitrile Column Phenomenex Gemini N-X C18, 10 um, 21.5 × 100mm Column temperature 25° C. LC gradient 5 to 85% in 10 min. LC Flowrate35 mL/min UV wavelength 254 nm Mass Spectrometer Waters 3100 IonizationES+

Method M

HPLC Waters mass-directed Mobile phase A 0.1% H₂O w/NH₄OH Mobile phase Bacetonitrile Column Phenomenex Gemini N-X C18, 10 um, 30 × 100 mm Columntemperature 25° C. LC gradient 5 to 50% in 15 min. LC Flowrate 60 mL/minUV wavelength 254 nm Mass Spectrometer Waters 3100 Ionization ES+

Method N Instrument: SHIMADZU LC/MS-2020

LC Parameters: Column: Shim-pack XR-ODS, 2.2 um, 3.0*50 mm; Mobile PhaseA: Water/0.05% o TFA; Mobile Phase B: Acetonitrile; Gradient: 5% B to100% B for 2.0 min, 100% B for 1.2 min, 100% B to 5% in 0.1 min, thenstop; Flow Rate: 1.0 mL/min; Column Temperature: 40° C.; Detector: UVand ELSD; Sample Preparation; 1 mg/mL in Methanol; Injection Volume: 1μL.MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.5 kv;Heat Block: 250° C.; Nebulizing Gas: 1.50 L/min; Scan Range: 70-900(m/z); Detector voltage: 1.1 kv.

Method O

Instrument SHIMADZU UHPLCMS-2020EV (LC-30AD pump, Binary solventmanager, SIL-AC Auto Samples, SPDM20A Detector, Alltech 3300 ELSDDetectorLC Parameters: Column: Shim-pack XR-ODS, 1.6 μm, 2.0*50 mm; Mobile PhaseA: Water/0.1% formic acid; Mobile Phase B: Acetonitrile/0.1% formicacid; Gradient: 5% B to 100% B for 2.0 min, 100% B for 1.1 min, 100% Bto 5% in 0.1 min, then stop; Flow Rate: 0.7 mL/min; Column Temperature:40° C.; Detector: Diode Array Detector (DAD) and ELSD; Injection Volume:1 μL.MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.0 kv;Heat Block: 200° C.; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900(m/z); Detector voltage: 0.9 kv.

Method P Instrument: SHIMADZU LC/MS-2020

LC Parameters: Column: Shim-pack XR-ODS, 2.2 um, 3.0*50 mm; Mobile PhaseA: Water/0.1% formic acid; Mobile Phase B: Acetonitrile/0.05% formicacid; Gradient: 5% B to 100% B for 2.0 min, 100% B for 1.1 min, 100% Bto 5% in 0.1 min, then stop; Flow Rate: 1.0 mL/min; Column Temperature:40° C.; Detector: PDA and ELSD; Sample Preparation: 1 mg/mL inacetonitrile; Injection Volume: 1 μL.MS Parameters: Interface: ESI (Positive); Interface Voltage: tuningfile; Heat Block: 250° C.; Nebulizing Gas: 1.50 L/min; Scan Range:90-900 (m/z); Detector voltage: 0.9 kv.

Method Q Instrument: SHIMADZU LC/MS-2020

LC Parameters: Column: Shim-pack XR-ODS, 2.2 um, 3.0*50 mm; Mobile PhaseA: Water/0.1% formic acid; Mobile Phase B: Acetonitrile/0.05% formicacid; Gradient: 5% B to 100% B for 2.0 min, 100% B for 1.2 min, 100% Bto 5% in 0.2 min, then stop; Flow Rate: 1.0 mL/min; Column Temperature:40° C.; Detector: UV and ELSD; Sample Preparation: 1 mg/mL inacetonitrile; Injection Volume: 1 μL.MS Parameters: Interface: ESI (Positive); Interface Voltage: 4.5 kv;Heat Block: 200° C.; Nebulizing Gas: 1.50 L/min; Scan Range: 90-900(m/z); Detector voltage: 0.95 kv.

Method R Instrument: SHIMADZU LC/MS-2020

LC Parameters: Column: Shim-pack XR-ODS, 2.2 um, 3.0*50 mm; Mobile PhaseA: Water/0.05% TFA; Mobile Phase B: Acetonitrile/0.05% TFA; Gradient: 5%B to 100% B for 1.2 min, 100% B for 0.9 min, 100% B to 5% in 0.2 min,then stop; Flow Rate: 1.0 mL/min; Column Temperature: 40° C.; Detector:PDA and ELSD; Sample Preparation: 1 mg/mL in acetonitrile; InjectionVolume: 1 μL.MS Parameters: Interface: ESI (Positive); Interface Voltage: tuningfile; Heat Block: 250° C.; Nebulizing Gas: 1.50 L/min; Scan Range:90-900 (m/z); Detector voltage: 1.1 kv.

Method S Instrument: SHIMADZU UHPLC/MS-2020

LC Parameters: Column: Shim-pack XR-ODS, 1.6 um, 2.0*50 mm; Mobile PhaseA: Water/0.1% formic acid; Mobile Phase B: Acetonitrile/0.05% formicacid; Gradient: 5% B to 100% B for 2.0 min, 100% B for 1.1 min, 100% Bto 5% in 0.1 min, then stop; Flow Rate 0.7 mL/min; Column Temperature:40° C.; Detector: PDA and ELSD; Sample Preparation: 1 mg/mL inacetonitrile; Injection Volume: 1 μL.MS Parameters: Interface: ESI (Positive); Interface Voltage: tuningfile; Heat Block: 250° C.; Nebulizing Gas: 1.50 L/min; Scan Range:90-900 (m/z); Detector voltage: 0.85 kv.

Method T Instrument: HPLC Agilent 1200

LC Parameters: Column: Agilent SB C18, 2.1*30 mm, 1.8 μm; Mobile PhaseA: Water/0.05% TFA; Mobile Phase B: Acetonitrile; Gradient: 3% B for 0.3min, 3% B to 95% B in 6.5 min, 95% B for 1.5 min, 95% to 3% B in 0.1min, then stop; Flow Rate: 0.4 mL/min; Column Temperature: 25° C.;Detector: 254 nm.

MS Parameters: Agilent 6140 Quadrupole LC/MS; Interface: ESI (Positive),Scan Range: 90-1300 amu. Method U Instrument: Waters Acquity UPLC

LC Parameters: Column: Acquity UPLC BEH C18, 1.7 mm, 2.1*50 mm; MobilePhase A: Water/0.05% TFA; Mobile Phase B: Acetonitrile; Gradient: 2% to98% B in 17.5 min, 98% B for 1.5 min, equilibrate for 1.5 min, thenstop; Flow Rate: 0.6 mL/min; Column Temperature: 40° C.; Detector: 254nm and 220 nm.MS Parameters: Waters LCT Premier XE; Interface: ESI (Positive); ScanRange: 80-1300 amu; Detector: Time of flight.

The following examples illustrate the preparation of representativecompounds of the invention. Unless otherwise specified, all reagents andsolvents were of standard commercial grade and were used without furtherpurification.

I. PREPARATION OF INTERMEDIATES Intermediate 1:Furo[2,3-c]pyridine-2-carboxylic acid

Step 1. Ethyl 3-hydroxyisonicotinate

A solution of 3-hydroxyisonicotinic acid (495 g, 3.56 mol) in ethanol (7L) and concentrated H₂SO₄ (250 mL) was heated under reflux for 72 h andthen cooled to rt and concentrated under reduced pressure to remove thesolvent. The residue was dissolved in water (3 L) and the pH wasadjusted to 4 by addition of saturated aqueous NaHCO₃ solution. Theresulting precipitate was removed by filtration and the filtrate wasextracted with DCM (2 L×3). The combined organic phase was washed withbrine, dried over anhydrous Na₂SO₄, and then concentrated under reducedpressure to give ethyl 3-hydroxyisonicotinate (414 g, 70%) as yellowoil.

Step 2. Ethyl 3-(2-ethoxy-2-oxoethoxy)isonicotinate

To a solution of triphenylphosphine (780 g, 2.97 mol) in THF (6 L) at−10° C. was added dropwise diisopropyl azodicarboxylate (600 mL, 2.97mol). The reaction mixture was stirred at −10° C. for 30 min and thenethyl 3-hydroxyisonicotinate (414 g, 2.48 mol) in THF (1 L) solution wasadded dropwise. The resulting mixture was stirred at rt for 16 h andthen concentrated under reduced pressure. The residue was partitionedbetween ethyl acetate (4 L) and 1 N HCl (2 L). The aqueous layer wasseparated and the organic phase was extracted by 1 N HCl (1 L×2). Thecombined aqueous layers were slowly adjusted to pH 8 by addition ofsolid NaHCO₃ and then extracted with ethyl acetate (2 L×2). The combinedorganic layers were dried over anhydrous Na₂SO₄ and then concentratedunder reduced pressure to give the title compound (380 g, 61%) as abrown oil.

Step 3. Ethyl 3-hydroxyfuro[2,3-c]pyridine-2-carboxylate

To a suspension of NaH (72 g, 1.8 mol, 60% suspension in mineral oil) inanhydrous THF (2 L) at 0° C. was added dropwise a solution of ethyl3-(2-ethoxy-2-oxoethoxy)isonicotinate (380 g, 1.5 mol) in THF (1 L)under argon. The reaction mixture was stirred at rt for 16 h and thencarefully quenched with ice water (1 L). The resulting mixture wasconcentrated to a volume of 1.2 L and then diluted with saturatedaqueous NaHCO₃ solution (2.5 L), and stirred for an additional 30 min.The precipitated solid was collected by filtration and washed with ethylacetate (1 L). The filtrate was washed with ethyl acetate (1 L×2) andthe aqueous layer was combined with the solid and carefully acidified toa pH of 5 with acetic acid. The resulting solid was collected byfiltration and dried under vacuum to give the title compound (210 g,68%) as a yellow solid.

Step 4. Ethyl3-(((trifluoromethyl)sulfonyl)oxy)furo[2,3-c]pyridine-2-carboxylate

To a solution of ethyl 3-hydroxyfuro[2,3-c]pyridine-2-carboxylate (210g, 1.01 mol) and pyridine (107 mL, 1.3 mol) in anhydrous DCM (3 L) at 0°C. was added dropwise triflic anhydride (203 g, 1.2 mol). The reactionmixture was stirred at rt for 16 h and then quenched with ice water (1L). The aqueous layer was extracted with DCM (1 L×2) and the combinedorganic layer was dried over anhydrous Na₂SO₄ and then concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography eluting with 10% ethyl acetate/petroleum ether to givethe title compound (298 g, 87%) as a white solid.

Step 5. Ethyl furo[2,3-c]pyridine-2-carboxylate

To a solution of ethyl3-(((trifluoromethyl)sulfonyl)oxy)furo[2,3-c]pyridine-2-carboxylate (298g, 0.88 mol) in ethanol (3 L) was added 10% Pd/C (30 g) andtriethylamine (281 mL, 2.02 mol). The reaction mixture was stirred underan atmosphere of hydrogen for 16 h and then filtered through a pad ofdiatomaceous earth. The filtrate was concentrated under reduced pressureand the residue was purified by silica gel column chromatography elutingwith 20% ethyl acetate/petroleum ether to give the title compound (158g, 94%) as a pale yellow solid.

Step 6

To a solution of ethyl furo[2,3-c]pyridine-2-carboxylate (158 g, 0.83mol) in water:THF:MeOH (1:1:1, 2.4 L) was added KOH (139 g, 2.49 mol).The reaction mixture was stirred at rt for 16 h and then concentrated toa volume of 750 mL. To this residue was added acetic acid until pH ˜4.The resulting solids were collected by filtration, washed with water(300 mL×2) and dried in a vacuum oven overnight to give the titlecompound (101 g, 75%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ 9.07 (s, 1H), 8.47 (d, J=5.6 Hz, 1H), 7.80 (d, J=5.2 Hz, 1H), 7.61 (s,1H). MS (ESI+) m/z: 164 [M+H]⁺.

Intermediate 2: Imidazo[1,2-a]pyridine-6-carboxylic acid

Step 1. Imidazo[1,2-a]pyridine-6-carboxylic acid hydrochloride salt

A mixture of 2-chloroacetaldehyde (277 g, 40%) and 6-aminonicotinic acid(150 g) in ethanol (330 mL) was heated to reflux and stirred for 8 h.After cooling, a solid precipitated and was isolated by vacuumfiltration, then washed with ethanol and dried under vacuum to give thetitle compound as a light yellow solid (1.78 g, 82%).

Step 2

Imidazo[1,2-a]pyridine-6-carboxylic acid hydrochloride salt (170 g) wasdiluted with water (600 mL) and heated until a clear solution resulted,then an aqueous solution of NaOH (2 M) was added slowly to adjust thepH=5-6. The reaction mixture was cooled to 0° C. using an ice-H₂O bath.The resulting precipitate was collected by vacuum filtration, thenwashed with ethanol and dried under vacuum to give the title product(107.2 g, 77%) as a light yellow powder. ¹H NMR (400 MHz, DMSO-d₆) δ13.76-12.82 (br, 1H), 9.28 (s, 1H), 8.10 (s, 1H), 7.68 (s, 1H),7.64-7.56 (m, 2H). MS (ESI+) m z: 163 [M+H]⁻.

Intermediate 3: Imidazo[1,2-a]pyrimidine-6-carboxylic acid

Step 1. Sodium (Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate

Methyl 3,3-dimethoxypropanoate (100 g, 675 mmol) and methyl formate (81g, 1350 mmol) were dissolved in anhydrous THF (450 mL). Sodium hydride(60% dispersion; 32.4 g, 810 mmol, 1.2 eq.) was then added slowly inportions at 0° C. The reaction mixture was stirred at rt for 1 h, thenwas heated at 50° C. for 3 h. During this period, H₂ evolution wasobserved. After cooling to rt, the solvent was then removed underreduced pressure to give the crude product which was directly used inthe next step without further purification.

Step 2. Methyl 2-aminopyrimidine-5-carboxylate

The crude enolate from step 1 was dissolved in DMF (200 mL), andguanidine hydrochloride (64 g, 670 mmol) was added. The mixture washeated at 100° C. under N₂ for 3 h. After cooling to rt, water was addedand the mixture was cooled with an ice-water bath. The resultingprecipitate was collected by vacuum filtration and dried under vacuum togive the desired product (63 g, 61% yield for 2 steps).

Step 3. Methyl imidazo[1,2-a]pyrimidine-6-carboxylate

To a mixture of 2-bromo-1,1-diethoxyethane (100.6 g, 0.51 mol) andmethyl 2-aminopyrimidine-5-carboxylate (63 g, 0.41 mol) in ethanol (300mL) was added concentrated HBr (40%) (55 g). The reaction mixture washeated to reflux for 3 h under N₂. After cooling to rt, the mixture wasfurther cooled with an ice-water bath. The resulting precipitate wascollected by vacuum filtration and dried under vacuum overnight to givethe desired product (92 g, 87%).

Step 4

Into a round bottom flask containing methylimidazo[1,2-a]pyrimidine-6-carboxylate (92 g, 356.5 mmol), was addedwater (200 mL). NaOH (6 N in H₂O, 2.5 eq.) was then added dropwise withstirring at rt. After stirring at rt for 1 h, the mixture was cooledwith an ice-water bath and concentrated HCl was added (pH=5-6). Theresulting mixture was concentrated under reduced pressure toapproximately 150 mL (3/4 volume) and cooled with an ice-water bath. Theresulting precipitate was collected by vacuum filtration, washed withcold water (50 mL) and dried to give the title compound as an off-whitesolid (46 g, 79%). ¹H NMR (DMSO-d₆, 400 MHz) δ 9.29 (d, J=2.0 Hz, 1H),8.89 (d, J=2.0 Hz, 1H), 7.94 (s, 1H), 7.70 (s, 1H). MS (m z. ES⁻): 164.1[M+H]⁺, 186.1 [M+Na]⁻.

Intermediate 4: 1H-Pyrazolo[3,4-b]pyridine-5-carboxylic acid

Step 1. 1-(4-Methoxybenzyl)-1H-pyrazol-5-amine

To a solution of acrylonitrile (30 mL, 455 mmol) in THF (250 mL),NH₂NH₂.H₂O (23.19 mL, 478 mmol) was added drop-wise at 0° C. Afteraddition was complete, the mixture was stirred at rt for 2 h, then4-methoxybenzaldehyde (55.4 mL, 455 mmol) was added drop-wise. Themixture was stirred at rt overnight, then at reflux for 2 h. Aftercooling to rt the mixture was quenched by addition of 300 mL of icewater. The mixture was extracted with ethyl acetate (3×), then thecombined organic layers were extracted with 1 N HCl. The aqueous layerwas neutralized with aqueous 10 N NaOH solution, then extracted withethyl acetate. The organic layer was washed with H₂O and brine, thendried over Na₂SO₄. Filtration, concentration, and recrystallization withEt₂O gave the target compound as a white solid (50 g, 60%).

Step 2. Ethyl4-hydroxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

1-(4-Methoxybenzyl)-1H-pyrazol-5-amine (3.94 g, 19.39 mmol), followed bydiethyl 2-(ethoxymethylene)malonate (4 mL, 20 mmol) was added to a 200mL round bottom flask fitted with a distillation head to remove ethanol.The mixture was heated to 130° C. for 45 min, then 10 mL of diphenylether was added and the temperature was raised to 240° C. for 2 h. Thereaction mixture was then cooled to rt and diethyl ether (100 mL) wasadded. The resulting precipitate was collected by vacuum filtration anddried under vacuum to afford the target compound as a white solid (4 g,62%).

Step 3. Ethyl4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

POCl₃ (10 mL) was added to ethyl4-hydroxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate(7.5 g, 19.39 mmol). The mixture was stirred at 60° C. for 3 h. Themixture was poured into ice water and the resulting precipitate wascollected by vacuum filtration and dried under vacuum to afford thetarget compound a light yellow solid (6.4 g, 80%).

Step 4. Ethyl1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

To a solution of ethyl4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate(5.9 g, 17 mmol) in THF (50 mL), triethylamine (1.7 g, 17 mmol),followed by Pd(OH)₂/C (300 mg) was added. The mixture was stirred at rtfor 3 h under H₂. The mixture was filtered and concentrated. The residuewas dissolved in ethyl acetate and washed with saturated aqueous NaHCO₃solution and brine, then dried over Na₂SO₄. Filtration and concentrationgave target compound as a light gray solid (5.3 g, 100%).

Step 5

Ethyl 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (4.4g, 14 mmol) was dissolved in TFA (158 mL) and heated to 80° C. Themixture was stirred at 80° C. for 4 h, then was concentrated to dryness.The residue was poured into ice water, then aqueous NaOH solution (2 M)was added until the pH was approximately 14. The solid formed wasremoved by filtration, and the aqueous layer was washed with ethylacetate. To the aqueous layer was added concentrated HCl was added untilthe pH was approximately 7 The resulting precipitate was collected byvacuum filtration and dried under vacuum to afford the title compound asa white solid (2.1 g, 80%). ¹H NMR (400 MHz, DMSO-d₆) δ 14.38-13.62 (br,1H), 9.07 (d, J=1.6 Hz, 1H), 8.81 (d, J=1.6 Hz, 1H), 8.32 (s, 1H). MS (mz, ESI+): 164 [M+H]⁺.

Intermediate 5: 1H-Pyrrolo[3,2-c]pyridine-2-carboxylic acid

Step 1. 3-Iodopyridin-4-amine

To a 2 L 3-necked flask was added a solution of 38 mL of concentratedsulfuric acid in 200 mL water. The solution was cooled with an ice-waterbath, then 4-aminopyridine (200 g, 2.12 mol) and acetic acid (700 mL)were added in batches. The mixture was then heated to reflux. Iodine(189 g, 0.745 mol) and periodic acid dihydrate (97 g, 0.424 mol) wereboth equally divided into four parts. One batch of iodine was added andthen one batch of periodic acid dihydrate was added 15 min later. After30 min, a new batch of iodine and periodic acid dihydrate were added inthe same way. When all four batches of iodine and periodic aciddehydrate were added, the mixture was kept refluxing for an additional 3h. After cooling to rt the reaction mixture was slowly poured into waterwhile stirring, then a 40% solution of NaOH in water was added untilpH >9. Na₂SO₃ was added to destroy the unreacted iodine. After coolingto rt, a filtration was performed. The collected solid was furtherpurified by recrystallization in chloroform to give the desired product(184 g, 39%).

Step 2

To a 2 L 3-necked flask was added DMF (700 mL), triethylene diamine (168g, 1.5 mol), and 4-amino-3-iodopyridine (24, 110 g, 0.5 mol). Themixture was cooled with an ice-water bath and pyruvic acid (132 g, 1.5mol) was slowly added, followed by palladium acetate (4.49 g, 0.02 mol).Under nitrogen atmosphere, the mixture was heated to 115° C. Thereaction generated effervescence. The reaction mixture was kept at115-120° C. for 11 h. The mixture was concentrated under reducedpressure. The residue was poured into water (500 mL), and concentratedHCl was added to adjust pH to <1. The mixture was cooled by adding iceand a filtration was performed. The cake thus obtained was a brownishblack solid.

The above cake was added into 500 mL of water. Concentrated HCl wasadded (to ensure complete protonation) followed by 5 g of active carbon.The mixture was heated to reflux for 20 min and then filtration wasperformed while hot. The solid was discarded and the hot filtrate wasplaced in a refrigerator to allow the HCl salt of the desired product toprecipitate. Upon cooling, filtration was performed which afforded adark brown solid with a wet weight of 48 g as the HCl salt of thedesired product.

The solid was then added to 250 mL of water and the mixture was heateduntil a clear solution resulted. Solid NaOH was slowly added to adjustpH to 5-6, then active carbon and an additional 500 mL of water wasadded. The mixture was heated to reflux for 30 min, then filtration wasperformed while hot. The resulting cake was added to 750 mL of water,heated to reflux, and filtered again. The cake thus obtained wasdiscarded. The two batches of filtrate were combined and cooled in arefrigerator. The resulting precipitate was collected by vacuumfiltration, then washed with ethanol to give the title compound as aslightly yellow solid (25 g, 31%). MS (m z, ES⁺): 161.1 [M−1], 323.1[2M−1]. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.20 (br s, 1H), 8.97 (s, 1H), 8.27(d, J=5.6 Hz, 1H), 7.41 (d, J=6.0 Hz, 1H), 7.23 (s, 1H).

Intermediate 6: Thieno[2,3-c]pyridine-2-carboxylic acid

Step 1. 3,5-Dibromoisonicotinaldehyde

Lithium diisopropylamide (507 mmol, 1.2 eq.) was added to 200 mL of dryTHF at −78° C. under N₂. A solution of 3,5-dibromopyridine (100 g, 424mmol) in 537 mL of dry THF was then added drop-wise over 30 min. Thereaction mixture was stirred at −78° C. for 1 h. Ethyl formate (34.4 g,465 mmol) was added drop-wise and stirred at −78° C. for 30 min, thenthe reaction mixture was poured into ice-cold saturated aqueous NaHCO₃solution. The mixture was extracted with 3×500 mL of ethyl acetate. Theorganic layer was concentrated to provide a brown solid, which wasfiltered through a pad of silica gel (eluted with dichloromethane) togive the title compound as a yellow powder (70 g, 63%).

Step 2: Methyl 4-bromothieno[2,3-c]pyridine-2-carboxylate

3,5-Dibromoisonicotinaldehyde (80 g, 303 mmol), followed by cesiumcarbonate (98 g, 302 mmol) was added to a 2 L round bottom flaskcontaining THF (1.3 L) under N₂. Methyl mercaptoacetate (32 g, 302 mmol)was added and the mixture was heated at 60° C. overnight. After coolingto rt, ethyl acetate was added and the organic layer was washed withwater, aqueous saturated NaHCO₃ solution, and brine, then dried overNa₂SO₄ and filtered to give a white solid. The crude product waspurified by recrystallization from ethyl acetate to give the desiredproduct (60 g, 73%).

Step 3. Methyl thieno[2,3-c]pyridine-2-carboxylate

Methyl 4-bromothieno[2,3-c]pyridine-2-carboxylate (115 g, 423 mmol),triethylamine (42.7 g, 423 mmol), THF (1.5 L), and MeOH (500 mL) weremixed and degassed. Under nitrogen, palladium on carbon (10%, 14.7 g,13.9 mmol) was added. The mixture was hydrogenated with a Parr apparatusat 45 psi H₂ for 3 days. The catalyst was filtered off and the filtratewas concentrated to give the desired compound as a white solid (65 g,80%).

Step 4

A three necked 2 L round bottom flask equipped with an overhead stirrerand thermocouple was charged with methylthieno[2,3-c]pyridine-2-carboxylate (130 g, 674 mmol) and water (650mL). Aqueous sodium hydroxide solution (10 N) was added with stirring at20° C. Over the next 20 min, the temperature rose to 25° C. and thesolid dissolved. After 1 h, concentrated HCl (1.5 eq.) was slowly addedto the reaction mixture with rapid stirring, generating a thick slurry.After stirring for 1 h, the slurry was filtered and the solid was driedunder vacuum to give the title compound as a white solid (105.5 g, 88%).MS (m/z, ES⁻): 178.0 [M−1]. ¹H-NMR (DMSO-d₆, 400 MHz) δ 12.24 (br s,1H), 8.97 (s, 1H), 8.27 (d, J=6.0 Hz, 1H), 7.40 (d, J=5.6 Hz, 1H), 7.23(s, 1H).

Intermediate 7: Imidazo[1,2-b]pyridazine-6-carboxylic acid

Step 1. 6-Chloro-imidazo[1,2-b]pyridazine

A solution of 6-chloro-1,2-diazinan-3-amine (10 g, 73.75 mmol, 1.00equiv), 2-bromo-1,1-dimethoxyethane (50 g, 295.83 mmol, 4.01 equiv), andHBr (40%, 45 mL) in ethanol (100 mL) was stirred overnight at 90° C. Themajority of the ethanol was removed under reduced pressure then the pHvalue of the solution was adjusted to 10 with 5% aqueous potassiumcarbonate solution. The resulting mixture was extracted with 6×500 mL ofethyl acetate. The combined organic layers were dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedon a silica gel column eluted with ethyl acetate/petroleum ether(1/2˜1/1) to give 6.5 g (57%) of the title compound as a yellow solid.¹H NMR (300 MHz, CDCl₃) δ 7.95 (s, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.05(d, J=9.3 Hz, 1H).

Step 2. Imidazo[1,2-b]pyridazine-6-carboxylic acid methyl ester

A mixture of 6-chloro-imidazo[1,2-b]pyridazine (200 mg, 1.30 mmol, 1.00equiv), bis(triphenylphosphine)palladium(II) dichloride (200 mg, 0.28mmol, 0.22 equiv), and triethylamine (0.5 mL) in methanol (4 mL) wasstirred under carbon monoxide (10 atm) in a 50-mL pressure reactorovernight at 110° C. The solid material was removed by filtration. Thefiltrate was concentrated under vacuum and the residue was purified on asilica gel column eluted with ethyl acetate/petroleum ether (1/1) togive 100 mg (43%) of the title compound as a yellow solid. ¹H NMR (300MHz, CDCl₃) δ 8.16 (s, 1H), 8.08 (d, J=9.6 Hz, 1H), 7.94 (s, 1H), 7.77(d, J=9.6 Hz, 1H), 4.09 (s, 3H).

Step 3

A mixture of imidazo[1,2-b]pyridazine-6-carboxylic acid methyl ester(900 mg, 5.08 mmol, 1.00 equiv) and 5% aqueous sodium hydroxide solution(15 mL, 3.75 equiv) in THF (3 mL) was stirred overnight at rt. The pHvalue of the solution was adjusted to 2 with 1 M HCl. The resultingmixture was concentrated under vacuum to give 3 g of crude title productas a yellow solid. The crude product was used without furtherpurification. LC/MS (Method A, ESI): RT=0.43 min, m z=164.0 [M+H]⁺.

Intermediate 8: Pyrazolo[1,5-a]pyridine-5-carboxylic acid

Step 1. 1-Amino-4-methoxypyridinium iodide

A solution of aminooxysulfonic acid (11.4 g, 100.80 mmol, 0.50 equiv)and 4-methoxypyridine (22 g, 201.60 mmol, 1.00 equiv) in water (200 mL)was stirred under nitrogen for 0.5 h at 90° C. Potassium carbonate (14g, 101.30 mmol, 0.50 equiv) was added at rt. The resulting mixture wasconcentrated under vacuum then ethanol (150 mL) was added to dissolvethe residue. The insoluble material was removed by filtration. Thefiltrate was cooled to −20° C. and then hydroiodic acid (16 g, 40%) wasadded. The resulting solution was stirred for 1 h at −20° C. Theprecipitated product was collected by filtration and washed with coldethanol to give 9.3 g (46%) of the title compound as a white solid. TLC:1:5 MeOH/DCM, R_(f)=0.02.

Step 2. 5-Methoxy-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester

A mixture of 1-amino-4-methoxypyridinium iodide (6 g, 23.80 mmol, 1.00equiv), potassium carbonate (5 g, 36.18 mmol, 1.50 equiv), and methylpropiolate (2 g, 23.79 mmol, 1.00 equiv) in DMF (50 mL) was stirredunder nitrogen for 4 h at rt. After the reaction completed, the mixturewas concentrated under vacuum. The residue was dissolved in 150 mL ofdichloromethane and then washed with 1×20 mL of saturated aqueous sodiumbicarbonate solution. The organic layer was concentrated under vacuumand the residue was purified on a silica gel column eluted with ethylacetate/hexane (1:3) to give 1.5 g (31%) of title product as a solid.LC/MS (Method D, ESI): RT=1.30 min, m z=207.0 [M+H]⁺.

Step 3. Pyrazolo[1,5-a]pyridin-5-ol

A mixture of methyl 5-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (100mg, 0.48 mmol, 1.00 equiv) in 40% HBr (5 mL) was stirred for 16 h at100° C. The reaction mixture was cooled to rt and the pH value of thesolution was adjusted to 8 with 5 M potassium hydroxide solution. Theresulting solution was extracted with 2×50 mL of ether. The organiclayers were combined and concentrated under vacuum. The residue waspurified on a silica gel column eluted with ethyl acetate/petroleumether (1:3 to 1:1) to yield 20 mg (31%) of the title compound as a whitesolid. LC/MS (Method D, ESI): RT=0.41 min, m z=135.0 [M+H].

Step 4. Trifluoro-methanesulfonic acid pyrazolo[1,5-a]pyridin-5-yl ester

A mixture of pyrazolo[1,5-a]pyridin-5-ol (300 mg, 2.24 mmol, 1.00 equiv)and trifluoromethanesulfonic anhydride (0.5 mL) in pyridine (5 mL) wasstirred for 10 h at rt. The resulting mixture was concentrated undervacuum and the residue was dissolved in 100 mL of dichloromethane. Themixture was washed with 1×10 mL of sodium bicarbonate solution. Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified on a silica gel column elutedwith ethyl acetate/petroleum ether (1:3) to yield 200 mg (34%) of thetitle compound as a solid. LC/MS (Method B, ESI): RT=2.13 min, m z=267.0[M+H]⁺.

Step 5. Pyrazolo[1,5-a]pyridine-5-carboxylic acid methyl ester

A mixture of trifluoro-methanesulfonic acid pyrazolo[1,5-a]pyridin-5-ylester (200 mg, 0.75 mmol, 1.00 equiv), triethylamine (227 mg, 2.24 mmol,3.00 equiv), DMSO (98 mg, 1.25 mmol, 1.67 equiv), andbis(triphenylphosphine)palladium(II) dichloride (53 mg, 0.08 mmol, 0.10equiv) in methanol (20 mL) was stirred under carbon monoxide (10 atm)for 16 h at 100° C. in a 50-mL pressure reactor. After the reactioncompleted, the reaction mixture was cooled to rt and the mixture wasconcentrated under vacuum. The residue was purified on a silica gelcolumn eluted with ethyl acetate/petroleum ether (1:3) to afford 130 mgof the title compound as a solid. LC/MS (Method H, ESI): RT=1.36 min, mz=177.0 [M+H]⁺.

Step 6

A mixture of pyrazolo[1,5-a]pyridine-5-carboxylic acid methyl ester (130mg, 0.74 mmol, 1.00 equiv) and potassium hydroxide (1 g, 17.82 mmol,24.15 equiv) in methanol (2 mL), THF (2 mL), and water (5 mL) wasstirred for 12 h at rt. The reaction mixture was washed with 2×50 mL ofethyl acetate. The aqueous layer was collected and the pH value of thesolution was adjusted to 6 with 1 N HCl. The solution was extracted with5×50 mL of ethyl acetate. The combined organic layers were dried overanhydrous sodium sulfate and concentrated under vacuum to give 100 mg(84%) the title compound as a yellow solid. LC/MS (Method G, ESI):RT=1.32 min, m z=163.0 [M+H].

Intermediate 9: 1H-Pyrazolo[4,3-b]pyridine-6-carboxylic acid

Step 1. 5-Bromo-2-methyl-pyridin-3-ylamine

To a stirred mixture of iron filings (5 g, 89.29 mmol, 3.88 equiv) andammonium chloride (1 g, 18.70 mmol, 0.81 equiv) in ethanol (66 mL) andwater (33 mL) was added a solution of 5-bromo-2-methyl-3-nitropyridine(5 g, 23.04 mmol, 1.00 equiv) in ethanol (50 mL) dropwise at 90° C. Thereaction mixture was stirred for 10 min at 90° C. and then cooled to rt.The solid material was removed by filtration. The filtrate wasconcentrated under vacuum and the residue was purified on a silica gelcolumn eluted with ethyl acetate/petroleum ether (1:2) to yield 1.6 g(37%) of the title compound as a yellow solid. LC/MS (Method I, ESI):RT=0.81 min, m z=187.0; 189.0 [M+H]⁻.

Step 2. N-(5-Bromo-2-methyl-pyridin-3-yl)-acetamide

A solution of 5-bromo-2-methyl-pyridin-3-ylamine (3 g, 16.04 mmol, 1.00equiv) in acetic anhydride (20 mL) and acetic acid (10 mL) was stirredovernight at rt. The resulting mixture was concentrated under vacuum togive 2.6 g (71%) of the title compound as a light yellow solid. LC/MS(Method I, ESI): RT=1.05 min, m z=229.0; 231.0 [M+H]⁺.

Step 3. 1-(6-Bromo-pyrazolo[4,3-b]pyridin-1-yl)-ethanone

A mixture of N-(5-bromo-2-methyl-pyridin-3-yl)-acetamide (3.5 g, 15.28mmol, 1.00 equiv), isopentyl nitrite (4 g, 34.73 mmol, 2.27 equiv),potassium acetate (20 g), and acetic anhydride (30 mL) in toluene (150mL) was stirred under nitrogen overnight at 90° C. The reaction mixturewas cooled to rt and the solid material was removed by filtration. Thefiltrate was concentrated under vacuum and the residue was purified on asilica gel column eluted with ethyl acetate/petroleum ether (1:5) togive in 2 g (55%) of the title compound as a light yellow solid. LC/MS(Method I, ESI): RT=1.44 min, m z=240.0; 242.0 [M+H]⁺.

Step 4. 1H-Pyrazolo[4,3-b]pyridine-6-carboxylic acid methyl ester

A mixture of 1-(6-bromo-pyrazolo[4,3-b]pyridin-1-yl)-ethanone (2 g, 8.33mmol, 1.00 equiv), bis(triphenylphosphine)palladium(II) dichloride (1 g,1.42 mmol, 0.17 equiv), and triethylamine (2.5 mL) in methanol (70 mL)was stirred overnight under carbon monoxide (10 atmospheres) at 100° C.in a 100 mL pressure reactor. The reaction mixture was cooled to rt andthe solid material was removed by filtration. The filtrate wasconcentrated under vacuum and the residue was purified on a silica gelcolumn eluted with ethyl acetate/petroleum ether (1:5) to afford 0.8 g(54%) of the title compound as a light yellow solid. TLC: 1:1 ethylacetate/petroleum ether, R_(f)=0.2.

Step 5

A solution 1H-pyrazolo[4,3-b]pyridine-6-carboxylic acid methyl ester(200 mg, 1.13 mmol, 1.00 equiv) and sodium hydroxide (200 mg, 5.00 mmol,4.43 equiv) in water (10 mL) was stirred overnight at rt. After thereaction was complete, the pH value of the solution was adjusted to 3with concentrated HCl. The resulting mixture was concentrated undervacuum to give 1 g of crude title product as a light yellow solid. LC/MS(Method I, ESI): RT=0.91 min, n z=164.0; 242.0 [M+H].

Intermediate 10: [1,2,4]Triazolo[1,5-a]pyridine-6-carboxylic acid

Step 1. N′-(5-Bromo-pyridin-2-yl)-N,N-dimethyl-formamidine

A solution of 5-bromopyridin-2-amine (4 g, 23.12 mmol, 1.00 equiv) andN,N-dimethylformamide dimethyl acetal (9.6 mL, 3.00 equiv) in DMF (30mL) was stirred under nitrogen for 12 h at 130° C. The reaction mixturewas cooled to rt and then concentrated under vacuum to give 4 g (76%) ofthe title compound as an oil. TLC: 1:5 MeOH/DCM, R_(f)=0.6.

Step 2. 6-Bromo-[1,2,4]triazolo[1,5-a]pyridine

To a solution of N′-(5-bromo-pyridin-2-yl)-N,N-dimethyl-formamidine (4g, 17.54 mmol, 1.00 equiv) in methanol (40 mL) maintained under nitrogenat 0° C. was added pyridine (4 mL, 2.00 equiv) and (aminooxy)sulfonicacid (3.6 g, 31.83 mmol, 1.30 equiv). The resulting solution was stirredfor 12 h at rt. After the reaction completed, the mixture wasconcentrated under vacuum. The residue was diluted with 150 mL of ethylacetate then washed with 1×50 mL of saturated aqueous sodium carbonatesolution and 2×50 mL of water. The organic layer was dried overanhydrous sodium sulfate then concentrated under vacuum. The residue waspurified on a silica gel column eluted with ethyl acetate/hexane (1:1)to give 2.5 g (72%) title compound as a solid. LC/MS (Method D, ESI):RT=1.15 min, m z=198.0 [M+H]⁺.

Step 3. [1,2,4]Triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester

A mixture of 6-bromo-[1,2,4]triazolo[1,5-a]pyridine (2.4 g, 12.12 mmol,1.00 equiv), bis(triphenylphosphine)palladium(II) dichloride (800 mg,1.14 mmol, 0.10 equiv) and triethylamine (4 g, 39.53 mmol, 3.00 equiv)in DMSO (1.6 g, 20.48 mmol, 1.67 equiv) and methanol (50 mL) was stirredunder carbon monoxide (10 atm) for 20 h at 100° C. The reaction mixturewas cooled to rt and quenched with brine (50 mL). The resulting solutionwas extracted with ethyl acetate (3×40 mL). The combined organic layerswere dried over anhydrous sodium sulfate then concentrated under vacuum.The residue was purified on a silica gel column eluted with ethylacetate/hexane (1:1) to give 0.98 g (46%) of the title compound as acrude solid. LC/MS (Method C, ESI): RT=1.04 min, m z=178.0 [M+H]⁺.

Step 4

A solution of [1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methylester (200 mg, 1.13 mmol, 1.00 equiv) in THF (2 mL) was added to asolution of potassium hydroxide (1 g, 17.82 mmol, 15.79 equiv) in water(10 mL). The resulting mixture was stirred for 10 h at rt. After thereaction completed, the pH value of the solution was adjusted to 5-6with 1 N HCl. The mixture was extracted with 3×50 mL of ethyl acetate.The combined organic layers were dried over anhydrous sodium sulfate andconcentrated under vacuum to give 112 mg (61%) of the title compound asa solid. LC/MS (Method C, ESI): RT=0.9 min, m z=164.0 [M+H]⁺.

Intermediate 11: Pyrazolo[1,5-a]pyrimidine-5-carboxylic acid

Step 1. 4H-Pyrazolo[1,5-a]pyrimidin-5-one

A solution of 1H-pyrazol-3-ylamine (7 g, 84.24 mmol, 1.00 equiv) andethyl prop-2-ynoate (50 mL) in dioxane (10 g, 1.21 equiv) was stirredunder nitrogen overnight at 110° C. The reaction mixture was cooled tort and the precipitated product was collected by filtration to give 4 g(36%) of the title compound as a light brown solid. ¹H NMR (300 MHz,DMSO-d₆) δ 12.04 (s, 1H), 8.41-8.44 (m, 1H), 7.71 (d, J=1.8 Hz, 1H),5.88 (d, J=8.1 Hz, 1H), 5.77 (m, 1H).

Step 2. 5-Chloro-pyrazolo[1,5-a]pyrimidine

A solution of 4H-pyrazolo[1,5-a]pyrimidin-5-one (1 g, 7.40 mmol, 1.00equiv) in phosphorus oxychloride (15 mL) was stirred under nitrogen for2 h at 120° C. The reaction mixture was cooled to rt then concentratedunder vacuum. The residue was purified on a silica gel column elutedwith ethyl acetate/petroleum ether (1:2) to give 0.6 g (53%) of thetitle compound as a light yellow solid. LC/MS (Method I, ESI): RT=1.21min, m z=154.0 [M+H]⁺.

Step 3. Pyrazolo[1,5-a]pyrimidine-5-carboxylic acid methyl ester

A mixture of 5-chloro-pyrazolo[1,5-a]pyrimidine (2 g, 13.02 mmol, 1.00equiv), triethylamine (4 mL), methanol (80 mL), andbis(triphenylphosphine)palladium(II) dichloride (1 g, 1.42 mmol, 0.11equiv) was stirred in a 100-mL pressure reactor overnight at 100° C.under 10 atmospheres of carbon monoxide. The reaction mixture was cooledto rt then concentrated under vacuum. The residue was purified on asilica gel column eluted with ethyl acetate/petroleum ether (1:5) toyield 1.2 g (52%) of the title compound as a light yellow solid. LC/MS(Method I, ESI): RT=1.09 min, m z=178.0 [M+H]⁺.

Step 4

To a solution of methyl pyrazolo[1,5-a]pyrimidine-5-carboxylic acidmethyl ester (100 mg, 0.56 mmol, 1.00 equiv) in acetic acid (5 mL) wasadded concentrated HCl (37%, 5 mL). The resulting solution was stirredfor 3 h at 120° C., then concentrated under vacuum. The residue wasdissolved in 3 mL of water and then adjusted to pH 5 with saturatedaqueous sodium carbonate solution. The precipitated product wascollected by filtration then air-dried to give 0.08 g (87%) ofpyrazolo[1,5-a]pyrimidine-5-carboxylic acid as a light yellow solid.LC/MS (Method I, ESI): RT=0.95 min, m z=164.0 [M+H]⁻.

Intermediate 12: 3-tert-Butylamino-imidazo[1,2-a]pyridine-6-carboxylicacid

Step 1. 3-tert-Butylamino-imidazo[1,2-a]pyridine-6-carboxylic acidmethyl ester

To a solution of methyl 6-aminopyridine-3-carboxylate (3.8 g, 24.98mmol, 1.00 equiv) and 2-oxoacetic acid hydrate (3.9 g, 42.39 mmol, 1.70equiv) in methanol (120 mL) was added perchloric acid (250 mg, 2.50mmol, 0.10 equiv). The reaction mixture was stirred for 30 min and2-isocyano-2-methylpropane (2.08 g, 25.02 mmol, 1.00 equiv) was thenadded. The reaction mixture was stirred for 12 h at rt and thenconcentrated under vacuum. The residue was purified on a silica gelcolumn eluted with dichloromethane/ethyl acetate (2:1) to give 850 mg(14%) of the title compound as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ8.97-8.96 (dd, J=0.9, 1.5 Hz, 1H), 7.69-7.65 (dd, J=4.2, 9.6 Hz, 1H),7.53-7.50 (dd, J=4.2, 9.6 Hz, 1H), 7.39 (s, 1H), 3.96 (s, 3H), 1.23 (s,9H).

Step 2. Sodium 3-tert-Butylamino-imidazo[1,2-a]pyridine-6-carboxylate

To a solution of 3-tert-butylamino-imidazo[1,2-a]pyridine-6-carboxylicacid methyl ester (300 mg, 1.21 mmol, 1.00 equiv) in methanol (5 mL) wasadded a solution of sodium hydroxide (97 mg, 2.42 mmol, 2.00 equiv) inwater (5 mL). The resulting solution was stirred for 1.5 h at 46° C. Thereaction mixture was cooled to rt and then quenched by the addition of0.15 mL of HCl. The resulting mixture was concentrated under vacuum togive 345.6 mg (crude) of the title product as a yellow solid. LC/MS(Method I, ESI): RT=1.02 min, m z=234.0 [M+H−22]⁻.

Step 3

Sodium 3-tert-butylamino-imidazo[1,2-a]pyridine-6-carboxylate (300 mg,1.17 mmol, 1.00 equiv) was dissolved in acetic acid (10 mL) and thenconcentrated under vacuum. The residue was purified on a silica gelcolumn eluted with dichloromethane/methanol (20:1) to give 150 mg (54%)of the title compound as a yellow solid. LC/MS (Method N, ESI): RT=0.94min, m/z=234.0 [M+H]⁺.

Intermediate 13: 2,3-Dihydro-1H-pyrrolo[3,4-c]pyridine

Step 1. Ethyl N-(prop-2-yn-1-yl)carbamate

To a solution of prop-2-yn-1-amine (11.5 g, 208.79 mmol, 1.00 equiv) andsodium hydroxide (9.1 g, 227.50 mmol, 1.09 equiv) in water (40 mL) andtoluene (110 mL) maintained under nitrogen was added ethyl chloroformate(23.9 g, 220.23 mmol, 1.05 equiv) dropwise in 20 min with stirring at10° C. The resulting solution was stirred overnight at rt then extractedwith 3×100 mL of toluene. The combined organic layers were dried overanhydrous sodium sulfate then concentrated under vacuum to give 15 g(57%) of ethyl N-(prop-2-yn-1-yl)carbamate as a light yellow oil. TLC:ethyl acetate/petroleum ether (1:2), R_(f)=0.5.

Step 2. Pyrimidine-5-carboxaldehyde

To a solution of 5-bromopyrimidine (2 g, 12.58 mmol, 1.00 equiv) in THF(20 mL) placed in a 50-mL 3-necked round-bottom flask purged andmaintained with an inert atmosphere of nitrogen was added n-butyllithium(1.1 mL) at −78° C. The reaction mixture was stirred at −78° C. foranother 2 h. Ethyl formate (5.2 mL) was then added and the resultingsolution was stirred for 2 h at −78° C. The resulting mixture was warmedto 0° C. and washed with 50 mL of brine. The organic layer was driedwith anhydrous sodium carbonate and concentrated. The residue waspurified on a silica gel column eluted with ethyl acetate/petroleumether (1:1) to give 11 g of crude pyrimidine-5-carboxaldehyde as ayellow oil. TLC: ethyl acetate/petroleum ether (1/1), R_(f)=0.2.

Step 3. Pyrimidin-5-ylmethanol

A mixture of pyrimidine-5-carboxaldehyde (2 g, 18.50 mmol, 1.00 equiv)and sodium borohydride (2 g) in methanol (100 mL) was stirred at 0-10°C. for 30 min. The reaction mixture was concentrated under vacuum andthe residue was purified on a silica gel column eluted withdichloromethane/methanol (50:1) to yield 1.2 g (59%) ofpyrimidin-5-ylmethanol as a light yellow solid. LC/MS (Method N, ESI):RT=0.74 min, m/z=111.0 [M+H]⁻.

Step 4. 5-(Chloromethyl)pyrimidine

To a solution of pyrimidin-5-ylmethanol (1.1 g, 10 mmol, 1.00 equiv) indichloromethane (30 mL) was added thionyl chloride (2 mL) dropwise withstirring. The resulting solution was stirred at rt for 2 h thenconcentrated in vacuum to give 1.1 g of crude 5-(chloromethyl)pyrimidineas a yellow oil. TLC: ethyl acetate/petroleum ether (1:1), R_(f)=0.4.

Step 5. Ethyl N-(prop-2-yn-1-yl)-N-(pyrimidin-5-ylmethyl)carbamate

A mixture of ethyl N-(prop-2-yn-1-yl)carbamate (1.27 g, 9.99 mmol, 1.00equiv) benzyltriethylammonium chloride (500 mg, 2.60 mmol, 0.26 equiv),5-(chloromethyl)pyrimidine (1.28 g, 9.96 mmol, 1.00 equiv) and potassiumhydroxide (3 g, 53.47 mmol, 5.37 equiv) in toluene (30 mL) was stirredovernight under nitrogen at rt. The resulting mixture was concentratedunder vacuum and the residue was purified on a silica gel column elutedwith ethyl acetate/petroleum ether (1:1) to afford 0.3 g (14%) of ethylN-(prop-2-yn-1-yl)-N-(pyrimidin-5-ylmethyl)carbamate as a light yellowoil. ¹H NMR (300 MHz, CDCl₃) δ 9.16 (s, 1H), 8.73 (s, 2H), 4.59 (s, 2H),4.11-4.26 (m, 4H), 2.28 (t, J=2.4 Hz, 1H), 1.30 (t, J=7.2 Hz, 3H).

Step 6. Ethyl 1H,2H,3H-Pyrrolo[3,4-c]pyridine-2-carboxylate

A mixture of ethyl N-(prop-2-yn-1-yl)-N-(pyrimidin-5-ylmethyl)carbamate(1 g, 4.56 mmol, 1.00 equiv) in xylene (30 mL) was stirred undernitrogen at 150° C. for 2 days. The resulting mixture was concentratedunder vacuum and the residue was purified on a silica gel column elutedwith ethyl acetate/petroleum ether (1/2) to give 0.4 g (46%) of ethyl1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxylate as a light brown crudesolid. ¹H NMR (300 MHz, CDCl₃) δ 8.53-8.93 (m, 2H), 7.24 (d, J=5.1 Hz,1H), 4.73-4.80 (m, 4H), 4.22-4.33 (m, 2H), 1.33-1.49 (m, 3H).

Step 7. 2,3-Dihydro-1H-pyrrolo[3,4-c]pyridine

A mixture of ethyl 1H,2H,3H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(400 mg, 2.4 mmol, 1.00 equiv) and barium hydroxide (0.8 g) in water(100 mL) was stirred overnight at 120° C. The reaction mixture wascooled to rt and the solid material was collected by filtration. Theresidue was stirred in hot ethyl acetate (150 mL) and then filtered toremove solid material. The filtrate was concentrated under vacuum togive 0.18 g (72%) of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine as a lightyellow oil. ¹H NMR (300 MHz, CDCl₃) δ 8.51 (s, 1H), 8.41-8.45 (t, J=4.8Hz, 1H), 7.13-7.20 (m, 1H), 4.25 (s, 2H), 4.22 (s, 2H).

Intermediate 14. 2H,4H,5H,6H-Pyrrolo[3,4-c]pyrazole hydrochloride

Step 1. tert-Butyl 2H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carboxylate

A solution of tert-butyl3-[(dimethylamino)methylidene]-4-oxopyrrolidine-1-carboxylate (1 g, 4.16mmol, 1.00 equiv) and hydrazine hydrate (340 mg, 6.79 mmol, 1.63 equiv)in ethanol (10 mL) was stirred at rt for 5 h. The resulting mixture wasconcentrated under vacuum and the residue was purified on a silica gelcolumn eluted with ethyl acetate/petroleum ether (1:5 to 1:2) to give250 mg (29%) of tert-butyl2H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carboxylate as a yellow solid.LC/MS (Method C, ESI): RT=1.30 min, m/z=210.0 [M+H]⁻.

Step 2

A solution of tert-butyl2H,4H,5H,6H-pyrrolo[3,4-c]pyrazole-5-carboxylate (250 mg, 1.19 mmol,1.00 equiv) in DCM (5 mL) and TFA (5 mL) was stirred overnight at rt.The resulting mixture was concentrated under vacuum and the residue wasdissolved in 20 mL of concentrated HCl. The resulting mixture wasconcentrated under vacuum to give 200 mg of crude2H,4H,5H,6H-pyrrolo[3,4-c]pyrazole hydrochloride as a dark red solid.LC/MS (Method C, ESI): RT=0.46 min, m/z=110.0 [M+H]⁻.

Intermediate 15. Lithium pyrazolo[1,5-b]pyridazine-5-carboxylate

Step 1. 4-Methoxypyridazine

A mixture of 3,6-dichloro-4-methoxypyridazine (30 g, 167.59 mmol, 1.00equiv), ammonium formate (31 g, 491.63 mmol, 2.93 equiv) and 10%palladium on carbon (3 g) catalyst in MeOH (500 mL) was stirred under 1atmosphere of hydrogen at rt overnight. The catalyst was removed byfiltration and the filtrate was concentrated under vacuum. The residuewas dissolved in 500 mL of DCM/MeOH (10:1). The solid material wasremoved by filtration. The filtrate was concentrated under vacuum andthe residue was purified on a silica gel column eluted with ethylacetate/petroleum ether (2:1 to 1:1) to give 15 g (81%) of4-methoxypyridazine as a brown oil. TLC: petroleum ether:ethylacetate=2:1, R_(f)=0.1.

Step 2. Methyl 5-methoxypyrazolo[1,5-b]pyridazine-3-carboxylate

To a stirred solution of hydroxylamine-O-sulfonic acid (30.8 g, 272.57mmol, 1.50 equiv) in water (100 mL) maintained under nitrogen at 5° C.was added a solution of potassium bicarbonate (29.1 g, 290.67 mmol, 1.60equiv) in water (100 mL) dropwise. The resulting mixture was stirred for10 min then a solution of 4-methoxypyridazine (20 g, 181.63 mmol, 1.00equiv) in water (100 mL) was added. The reaction mixture was stirred at70° C. for 5 h and then cooled back to rt. A solution of methylprop-2-ynoate (16.8 g, 199.83 mmol, 1.10 equiv) in DCM (500 mL) followedby a solution of potassium hydroxide (17.3 g, 308.32 mmol, 1.70 equiv)in water (100 mL) were added to the reaction mixture. The resultingsolution was stirred overnight at rt then extracted with 4000 mL of DCM.The organic layer was washed with 3×500 mL of brine, dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified on a silica gel column eluted with ethyl acetate/petroleumether (6:1 to 2:1) to give 1 g (3%) of methyl5-methoxypyrazolo[1,5-b]pyridazine-3-carboxylate as a brown solid. TLC:petroleum ether:ethyl acetate=1:1, R_(f)=0.4.

Step 3. Pyrazolo[1,5-b]pyridazin-3-ol

A solution of methyl 5-methoxypyrazolo[1,5-b]pyridazine-3-carboxylate (2g, 9.65 mmol, 1.00 equiv) in 40% hydrobromic acid (50 mL) was refluxedovernight. The resulting mixture was cooled to rt then concentratedunder vacuum. The residue was dissolved in 50 mL of H₂O and the pH valueof the solution was adjusted to 6-7 with saturated aqueous KHCO₃solution (50 mL). The mixture was concentrated and the residue waspurified on a silica gel column eluted with DCM:MeOH (10:1) to give 500mg (38%) of pyrazolo[1,5-b]pyridazin-3-ol as a brown solid. LC/MS(Method D, ESI): RT=0.41 min, m z=136.0 [M+H]⁻.

Step 4. Pyrazolo[1,5-b]pyridazin-3-yl trifluoromethanesulfonate

To a solution of pyrazolo[1,5-b]pyridazin-3-ol (450 mg, 3.33 mmol, 1.00equiv) and pyridine (1.1 g, 13.91 mmol, 3.00 equiv) in DCM (20 mL)maintained under nitrogen at −5° C. was added trifluoromethanesulfonicanhydride (1.9 g, 6.73 mmol, 2.02 equiv) dropwise with stirring in 20min. The resulting solution was stirred for another 60 min at 0° C. andthen diluted with 200 mL of DCM. The mixture was washed with 3×100 mL ofbrine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified on a silica gel column eluted withethyl acetate/petroleum ether (1:10 to 1:5) to give 570 mg (64%) ofpyrazolo[1,5-b]pyridazin-3-yl trifluoromethanesulfonate as a whitesolid. TLC: petroleum ether:ethyl acetate=1:1, R_(f)=0.2.

Step 5. Methyl pyrazolo[1,5-b]pyridazine-3-carboxylate

A mixture of 4aH,5H-pyrazolo[1,5-b]pyridazin-3-yltrifluoromethanesulfonate (600 mg, 2.23 mmol, 1.00 equiv), Pd(PPh₃)₂Cl₂(300 mg, 0.43 mmol, 0.19 equiv) and pyridine (530 mg, 6.70 mmol, 3.01equiv) in DMF (20 mL) and MeOH (5 mL) was stirred under 10 atmosphere ofCO in a 50-mL pressure tank reactor overnight at 80° C. The reactionmixture was cooled to rt then diluted with 100 mL of H₂O. The resultingsolution was extracted with 3×100 mL of ethyl acetate. The combinedorganic layers were washed with 3×100 mL of brine, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedon a silica gel column eluted with ethyl acetate/petroleum ether (1:5)to yield 200 mg (51%) of methyl pyrazolo[1,5-b]pyridazine-3-carboxylateas a yellow solid. TLC: petroleum ether:ethyl acetate=2:1, R_(f)=0.4.

Step 6

To a solution of methyl pyrazolo[1,5-b]pyridazine-3-carboxylate (60 mg,0.34 mmol, 1.00 equiv) in THF (5 mL) was added a solution of LiOH (40mg, 1.667 mmol, 1.7 equiv) in water (1 mL). The reaction mixture wasstirred overnight at 50° C. and then concentrated under vacuum to give150 mg of crude lithium pyrazolo[1,5-b]pyridazine-5-carboxylate as adark red solid.

Intermediate 16: 2-(6-Aminopyridin-3-yl)acetic acid

Step 1. 1,3-Diethyl 2-(6-nitropyridin-3-yl)propanedioate

A mixture of 5-bromo-2-nitropyridine (2 g, 9.85 mmol, 1.00 equiv),1,3-diethyl propanedioate (8 g, 49.95 mmol, 5.07 equiv), sodium hydride(1.2 g, 50.00 mmol, 5.07 equiv), L-proline (0.1 g) and CuI (100 mg, 0.53mmol, 0.05 equiv) in DMF (100 mL) was stirred under nitrogen at 100° C.for 20 h. The reaction was cooled to rt and then concentrated undervacuum. The mixture was diluted with 300 mL of ethyl acetate and thenwashed with 3×50 mL of H₂O. The organic layer was dried over anhydroussodium sulfate, filtered and concentrated to give 2 g of crude1,3-diethyl 2-(6-nitropyridin-3-yl)propanedioate as red oil. TLC: ethylacetate/petroleum ether=1/1, R_(f)=0.4.

Step 2. 1,3-Diethyl 2-(6-aminopyridin-3-yl)propanedioate

A mixture of 1,3-diethyl 2-(6-nitropyridin-3-yl)propanedioate (1.5 g,5.31 mmol, 1.00 equiv) and Raney Ni (1 g) in MeOH (30 mL) was stirredunder 1 atmosphere of H₂ at rt for 2 h. The catalyst was removed byfiltration and the filtrate was concentrated under vacuum. The residuewas purified on a silica gel column eluted with DCM/MeOH (5:1) to afford1.3 g of crude 1,3-diethyl 2-(6-aminopyridin-3-yl)propanedioate as ayellow oil. TLC: dichloromethane/MeOH=5/1; R_(f)=0.5.

Step 3. Ethyl 2-(6-aminopyridin-3-yl)acetate

A mixture of 1,3-diethyl 2-(6-aminopyridin-3-yl)propanedioate (1.2 g,4.76 mmol, 1.00 equiv) and lithium chloride (600 mg, 14.15 mmol, 2.98equiv) in DMSO (10 mL) and water (1 mL) was stirred under nitrogen at130° C. for 18 h. The reaction was cooled to rt and then diluted with200 mL of ethyl acetate. The mixture was washed with 3×50 mL of H₂O. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified on a silica gelcolumn eluted with ethyl acetate/hexane (1/1) to give 200 mg (23%) ofethyl 2-(6-aminopyridin-3-yl)acetate as a light yellow oil. TLC:DCM/MeOH=5:1; R_(f)=0.6.

Step 4

To a solution of ethyl 2-(6-aminopyridin-3-yl)acetate (200 mg, 1.11mmol, 1.00 equiv) in ethanol (5 mL) was added a solution of potassiumhydroxide (200 mg, 3.56 mmol, 3.21 equiv) in water (5 mL). The reactionmixture was stirred under nitrogen at rt for 11 h. The pH value of thesolution was adjusted to 6 with 2 M HCl. The resulting mixture wasconcentrated under vacuum to give 0.5 g of crude2-(6-aminopyridin-3-yl)acetic acid as an off-white solid. TLC:DCM/MeOH=5/1; R_(f)=0.2.

Intermediate 17. 1H,2H,3H-Pyrrolo[3,4-c]pyridin-6-amine

Step 1. 6-Chloropyridine-3-carbonyl chloride

A mixture of 6-chloropyridine-3-carboxylic acid (20 g, 126.94 mmol, 1.00equiv), DMF (1 g, 13.68 mmol, 0.11 equiv) and thionyl chloride (20 mL)in toluene (200 mL) was stirred under nitrogen for 3 h at 80° C. Theresulting solution was cooled to rt and concentrated under vacuum togive 25 g of crude 6-chloropyridine-3-carbonyl chloride as a lightyellow solid.

Step 2. 6-Chloro-N,N-bis(propan-2-yl)pyridine-3-carboxamide

To a solution of 6-chloropyridine-3-carbonyl chloride (25 g, 142.05mmol, 1.00 equiv) in DCM (500 mL) maintained under nitrogen at 0° C. wasadded diisopropylamine (50 g, 494.12 mmol, 3.48 equiv) dropwise withstirring. The reaction mixture was stirred for 50 min at 25° C. and thenquenched with the addition of H₂O (300 mL). The organic layer wascollected and the aqueous layer was extracted with 2×300 mL of DCM. Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under vacuum to give 25 g (73%) of6-chloro-N,N-bis(propan-2-yl)pyridine-3-carboxamide as a light yellowsolid. TLC: ethyl acetate:petroleum ether=1:2, R_(f)=0.4.

Step 3. 6-Chloro-4-formyl-N,N-bis(propan-2-yl)pyridine-3-carboxamide

To a stirred solution of diisopropylamine (1 g, 9.88 mmol, 4.76 equiv)in ether (30 mL) at −50° C. maintained under nitrogen was added a 2.5Msolution of n-BuLi (5 mL) in hexanes dropwise. The reaction mixture wasstirred for 30 min a −50° C. then solid6-chloro-N,N-bis(propan-2-yl)pyridine-3-carboxamide (500 mg, 2.08 mmol,1.00 equiv) was added in a single portion. The resulting solution wasstirred for 30 min at −50° C. DMF (1 mL) was then added dropwise withstirring. The reaction mixture was stirred at −50° C. for 3 h and thenwarmed to rt and stirred overnight. The reaction was quenched by theaddition of 10% aqueous citric acid solution (30 mL) and then extractedwith 2×50 mL of ether. The combined organic layers was dried overanhydrous sodium sulfate and concentrated under vacuum to give 0.5 g ofcrude 6-chloro-4-formyl-N,N-bis(propan-2-yl)pyridine-3-carboxamide as ayellow solid. LC/MS (Method G, ESI): RT=1.40 min, m/z=269.0 [M+H]⁺.

Step 4.6-Chloro-4-(hydroxymethyl)-N,N-bis(propan-2-yl)pyridine-3-carboxamide

A mixture of6-chloro-4-formyl-N,N-bis(propan-2-yl)pyridine-3-carboxamide (500 mg,1.86 mmol, 1.00 equiv) and NaBH₄ (500 mg, 13.22 mmol, 7.10 equiv) inethanol (50 mL) was stirred for 50 min at 30° C. The reaction was thenquenched by the addition of 1M HCl. The solid was removed by filtrationand the filtrate was concentrated to provide 0.5 g of crude6-chloro-4-(hydroxymethyl)-N,N-bis(propan-2-yl)pyridine-3-carboxamide asa light yellow solid. LC/MS (Method F, ESI): RT=1.25 min, m/z=271.0[M+H]⁺.

Step 5. 6-Chloro-1H,3H-furo[3,4-c]pyridin-3-one

A mixture of6-chloro-4-(hydroxymethyl)-N,N-bis(propan-2-yl)pyridine-3-carboxamide (2g, 7.39 mmol, 1.00 equiv) in 6M HCl (40 mL) was stirred for 30 min at100° C. The reaction mixture was cooled to rt and the pH of the solutionwas adjusted to 8 with sodium carbonate. The mixture was extracted with200 mL of DCM. The organic layer was dried over anhydrous sodium sulfateand concentrated under vacuum to yield 1 g of crude6-chloro-1H,3H-furo[3,4-c]pyridin-3-one as a light yellow solid. LC/MS(Method R, ESI): RT=1.13 min, m z=170.0 [M+H]⁺.

Step 6. [6-Chloro-4-(hydroxymethyl)pyridin-3-yl]methanol

A mixture of 6-chloro-1H,3H-furo[3,4-c]pyridin-3-one (1 g, 5.90 mmol,1.00 equiv) and NaBH₄ (0.5 g) in ethanol (50 mL) was stirred for 60 mmat 25° C. The pH of the solution was adjusted to 1 with 6M HCl. Thesolid was removed by filtration and the filtrate was concentrated undervacuum. The residue was purified on a silica gel column eluted withDCM/MeOH (20:1) to give 0.4 g (39%) of[6-chloro-4-(hydroxymethyl)pyridin-3-yl]methanol as a light yellowsolid. LCMS (Method R, ESI): RT=0.95 min, m z=174.0 [M+H]⁺.

Step 7. 2-Chloro-4,5-bis(chloromethyl) pyridine hydrochloride

A mixture of [6-chloro-4-(hydroxymethyl)pyridin-3-yl]methanol (100 mg,0.58 mmol, 1.00 equiv) and thionyl chloride (2 mL) in DCM (20 mL) wasstirred under nitrogen at rt for 1 h. The resulting mixture wasconcentrated under vacuum to give 0.1 g of crude2-chloro-4,5-bis(chloromethyl)pyridine hydrochloride as a dark redsolid.

Step 8.6-Chloro-2-[(2,4-dimethoxyphenyl)methyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine

A mixture of 2-chloro-4,5-bis(chloromethyl)pyridine hydrochloride (I g,4.05 mmol, 1.00 equiv), (2,4-dimethoxyphenyl) methanamine (1 g, 5.98mmol, 1.48 equiv) and DIPEA (1 g, 7.74 mmol, 1.91 equiv) in DCM (60 mL)was stirred under nitrogen overnight at rt. The resulting mixture wasconcentrated under vacuum and the residue was purified on a silica gelcolumn eluted with ethyl acetate/petroleum ether (2:1) to give 0.9 g ofcrude6-chloro-2-[(2,4-dimethoxyphenyl)methyl]-1H,2H,3H-pyrrolo[3,4-c]pyridineas a reddish oil. LC/MS (Method R, ESI): RT=0.94 min, m z=305.0 [M+H]⁺.

Step 9.N,2-bis[(2,4-Dimethoxyphenyl)methyl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-amine

A mixture of6-chloro-2-[(2,4-dimethoxyphenyl)methyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine(200 mg, 0.66 mmol, 1.00 equiv), Pd₂(dba)₃.CHCl₃ (0.1 g), t-BuONa (200mg, 2.08 mmol, 3.17 equiv), BINAP (100 mg, 0.16 mmol, 0.24 equiv) and(2,4-dimethoxyphenyl)methanamine (400 mg, 2.39 mmol, 3.65 equiv) intoluene (20 mL) was stirred under nitrogen overnight at 80° C. Theresulting solution was diluted with 20 mL of H₂O and extracted with 2×50mL of ethyl acetate. The combined organic layers was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified on a silica gel column eluted with ethyl acetate/petroleumether (1:1) to give 0.2 g (70%) ofN,2-bis[(2,4-dimethoxyphenyl)methyl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-amineas a dark red solid. LC/MS (Method R, ESI): RT=0.92 min, m z=436.0[M+H]⁺.

Step 10

A solution ofN,2-bis[(2,4-dimethoxyphenyl)methyl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-amine(300 mg, 0.69 mmol, 1.00 equiv) in TFA (20 mL) was stirred undernitrogen overnight at 90° C. The resulting mixture was concentratedunder vacuum to remove most of the TFA. The pH of the residue wasadjusted to 8 with saturated sodium carbonate solution. The mixture wasconcentrated under vacuum and the residue was dissolved in hot ethylacetate and filtered. The filtrate was concentrated under reducedpressure to provide 0.15 g of crude1H,2H,3H-pyrrolo[3,4-c]pyridin-6-amine as a red oil LC/MS (Method R,ESI): RT=0.18 min, m z=136.0 [M+H]⁺.

Intermediate 18. 2,3-Dihydro-1H-pyrrolo[3,4-c]pyridine-d₄ hydrochloride

Step 1. 3,4-Dimethyl pyridine-3,4-dicarboxylate

To a solution of pyridine-3,4-dicarboxylic acid (35 g, 209.43 mmol, 1.00equiv) in MeOH (250 mL) was added concentrated sulfuric acid (55 mL)dropwise with stirring at rt. The resulting solution was stirred at 100°C. overnight. The reaction mixture was cooled to rt and thenconcentrated under vacuum. The residue was diluted with 500 mL of H₂Oand the pH of the solution was adjusted to 8 with 2M aqueous sodiumcarbonate solution. The resulting mixture was extracted with 3×300 mL ofDCM. The combined organic layers were washed with 3×500 mL, of brine,dried over anhydrous sodium sulfate and concentrated under vacuum togive 30 g (73%) of 3,4-dimethyl pyridine-3,4-dicarboxylate as a yellowoil. LC/MS (Method R, ESI): RT=1.23 min, m z=195.0 [M+H]⁺.

Step 2. 3,4-bis(Hydroxymethyl)pyridine-d₄ hydrochloride

To a stirred solution of NaBD₄ (4.3 g, 102.38 mmol, 4.00 equiv) in EtOD(15 mL) maintained under nitrogen at 0° C. was added dropwise a solutionof 3,4-dimethyl pyridine-3,4-dicarboxylate (5.0 g, 25.62 mmol, 1.00equiv) in EtOD (10 mL) followed by a solution of CaCl₂ (2.5 g, 22.73mmol, 0.90 equiv) in EtOD (20 mL) dropwise at 0° C. The reaction mixturewas stirred for 3 h while the reaction temperature was maintainedbetween 0 to 10° C. by an ice/water bath. The resulting mixture wasconcentrated under vacuum and the residue was dissolved in 200 mL ofethanol. The solid material was removed by filtration. The filtrate wascooled to 0° C. then hydrogen chloride gas was bubbled into the solutionwhile keeping the reaction temperature below 5° C. with an ice/waterbath. The resulting solution was stirred at 0-10° C. for 2 h. Thereaction mixture was concentrated under vacuum and the residue wastriturated in 100 mL of THF. The solid was collected by filtration anddried in vacuum to give 2.9 g of crude 3,4-bis(hydroxymethyl)pyridine-d₄hydrochloride as a white solid. ¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 9.00(d, J=2.1 Hz, 1H), 8.70 (s, 1H), 8.07 (d, J=6.0 Hz, 1H).

Step 3. 2-(2,4-Dimethoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-d₄

To a solution of 3,4-bis(hydroxymethyl)pyridine-d₄ hydrochloride (3.0 g,1.00 equiv) in DCM (80 mL) maintained under nitrogen at −5° C. was addeddropwise triethylamine (10 mL, 5.00 equiv) followed by methanesulfonylchloride (4.5 mL, 3.00 equiv) in 5 min. The reaction mixture was stirredat 0° C. for 1 h. The reaction was then quenched by the addition of 20mL of water and the resulting mixture was extracted with 2×50 mL of DCM.The combined organic layers was washed with 1×200 mL of brine, driedover anhydrous sodium sulfate and filtered. The filtrate was cooled to0° C. then DIPEA (5 mL, 2.0 equiv) followed by(2,4-dimethoxyphenyl)methanamine (3 mL, 1.10 equiv) was added dropwiseat 0° C. within 5 min. The resulting solution was stirred at rt for 8 h.The reaction was then quenched by the addition of 20 mL of water. Theresulting mixture was washed with 1×200 mL of water and 2×200 mL ofbrine. The organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified on a silica gelcolumn eluted with DCM/MeOH (96/4) to give 1.4 g of crude as2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-d₄ as ared oil.

Step 4

A solution of2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-d₄ (700mg, 2.04 mmol, 1.00 equiv, 80%) in CF₃COOD (5 mL) was stirred at 70° C.for 10 h. The resulting mixture was concentrated under vacuum and theresidue was dissolved in 50 mL of DCM. Hydrogen chloride gas was bubbledinto the stirred reaction mixture at 0° C. for 30 min. The precipitatewas collected by filtration and dried in vacuum to give 600 mg of crude2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-d4 hydrochloride as a yellowsolid. ¹H-NMR (400 MHz, D₂O, ppm): δ 8.77 (s, 1H), 8.69 (d, J=6.0 Hz,1H), 8.00 (d, J=6.0 Hz, 1H).

II. PREPARATION OF EXAMPLE COMPOUNDS Example 1 tert-Butyl2-[(1,3-dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-8-azaspiro[2,5]octane-8-carboxylate

Step 1.1-[[(4-Nitrophenoxycarbonyl)amino]methyl]-6-azaspiro[2.5]octane-6-carboxylate

A solution of 4-nitrophenyl chloroformate (42.5 g, 210.85 mmol, 1.00equiv) and tert-butyl1-(aminomethyl)-6-azaspiro[2.5]octane-6-carboxylate (50 mg, 0.21 mmol)in toluene (5 mL) was stirred at 120° C. for 1 h. The resulting mixturewas concentrated under vacuum to give 50 mg of tert-butyl1-[[(4-nitrophenoxycarbonyl)amino]methyl]-6-azaspiro[2.5]octane-6-carboxylateas a yellow solid. LC/MS (Method K, ESI): RT=2.02 min, m/z=407.0 [M+H]⁻.

Step 2. tert-Butyl2-[(1,3-dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-8-azaspiro[2.5]octane-8-carboxylate

A solution of tert-butyl1-[[(4-nitrophenoxycarbonyl)amino]methyl]-6-azaspiro[2.5]octane-6-carboxylate(81 mg, 0.20 mmol, 1.00 equiv) and 2,3-dihydro-H-pyrrolo[3,4-c]pyridine(25 mg, 0.21 mmol, 1.04 equiv) in ethanol (5 mL) was stirred for 1 h at80° C. The resulting mixture was concentrated under vacuum and theresidue was purified on a silica gel column eluted withdichloromethane/methanol (10/1) to yield 8.9 mg (12%) of the titlecompound as an off-white solid. LC/MS (Method H, ESI): RT=1.40 min, mz=387.0 [M+H]⁻. ¹H NMR (300 MHz, CD₃OD) δ 8.55 (s, 1H), 8.47-8.46 (d,J=5.1 Hz, 1H), 7.46-7.44 (d, J=5.1 Hz, 1H), 4.76 (s, 2H), 3.64-3.54 (m,2H), 3.37 (s, 2H), 3.27-3.20 (m, 2H), 1.70-1.63 (m, 1H), 1.46 (s, 11H),1.25-1.19 (m, 1H), 1.07-1.05 (m, 1H), 0.62-0.53 (m, 1H), 0.32-0.21 (m,1H).

Example 6N-[[8-(3,3-dimethylbutanoyl)-8-azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide

Step 1. tert-Butyl2-[(1H-pyrrolo[3,2-c]pyridine-2-carbonylamino)methyl]-8-azaspiro[2.5]octane-8-carboxylate

A solution of tert-butyl1-(aminomethyl)-6-azaspiro[2.5]octane-6-carboxylate (1750 mg, 7.28 mmol,1.00 equiv), 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (1299 mg, 8.01mmol, 1.10 equiv), EDCI (2786 mg, 14.53 mmol, 2.00 equiv), triethylamine(2946 mg, 29.11 mmol, 4.00 equiv), and HOBt (1181 mg, 8.74 mmol, 1.20equiv) in DMF (30 mL) was stirred overnight at room temperature. Theresulting solution was diluted with 100 mL of water and extracted with3×100 mL of ethyl acetate. The combined organic layers were washed with3×200 mL of brine, dried over anhydrous sodium sulfate, and concentratedunder vacuum to afford 2.3 g (82%) of the title compound as a red oil.LC/MS (Method C, ESI): RT=1.29 min, m z=385.0 [M+H]⁺.

Step 2.N-(8-azaspiro[2.5]octan-2-ylmethyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamidetrifluoroacetate salt

A solution of tert-butyl2-[(1H-pyrrolo[3,2-c]pyridine-2-carbonylamino)methyl]-8-azaspiro[2.5]octane-8-carboxylate(3.2 g, 8.32 mmol, 1.00 equiv) in TFA (10 mL) and dichloromethane (10mL) was stirred for 3 h at room temperature. The resulting mixture wasconcentrated under vacuum to give 4 g of crude title product as a brownoil. LC/MS (Method E, ESI): RT=0.96 min, m z=285.0 [M+H]⁺.

Step 3

To a solution ofN-(8-azaspiro[2.5]octan-2-ylmethyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamidetrifluoroacetate salt (179 mg, 0.44 mmol, 1.00 equiv) and triethylamine(136 mg, 1.32 mmol, 3.01 equiv) in dichloromethane (5 mL) at 0° C. wasadded 3,3-dimethylbutanoyl chloride (60 mg, 0.44 mmol, 1.00 equiv)dropwise with stirring. The resulting solution was stirred for 1 h atroom temperature. The reaction mixture was diluted with 20 mL ofdichloromethane, washed with 2×10 mL of brine, then dried over anhydroussodium sulfate and concentrated under vacuum. The crude product (110 mg)was purified by preparative HPLC (Instrument, Waters 2767-2; Column,sunfire-C18; mobile phase, water with NH₄HCO₃ (1 g/L) and CH₃CN (25%CH₃CN up to 57% in 10 min); Detector, UV 254 nm) to give 2.3 mg (1%) ofthe title compound as a white solid. LC/MS (Method H, ESI): RT=1.95 min,m z=383.0 [M+H]⁺. ¹H NMR (400 Hz, CDCl₃) δ 9.02 (s, 1H), 8.42-8.41 (d,J=4.8 Hz, 1H), 7.54 (m, 1H), 7.01 (s, 1H), 6.48 (m, 1H), 4.10-4.09 (m,1H), 3.67-3.32 (m, 5H), 2.35-2.25 (m, 2H), 1.63-1.50 (m, 2H), 1.28-1.22(m, 1H), 1.07 (s, 11H), 0.71 (s, 1H), 0.39 (s, 1H).

Example 150N-([6-[2-(3-methyloxetan-3-yl)acetyl]-6-azaspiro[2.5]octan-1-yl]methyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide

Step 1. Ethyl 2-(oxetan-3-ylidene)acetate

A solution of oxetan-3-one (2.0 g, 27.75 mmol, 1.00 equiv) and(ethoxycarbonylmethylene)triphenylphosphorane (10.2 g, 29.28 mmol, 1.10equiv) in DCM (40 mL) was stirred at 0° C. for 30 min. The reactionmixture was concentrated under vacuum and the residue was triturated in200 mL of petroleum ether. The solid material was removed by filtration.The filtrate was concentrated under vacuum to give 3.3 g of crude ethyl2-(oxetan-3-ylidene)acetate as a colorless liquid. LC/MS (Method A,ESI): RT=1.32 min, m z=143.0 [M+H]⁻.

Step 2. Ethyl 2-(3-methyloxetan-3-yl)acetate

To a solution of ethyl 2-(oxetan-3-ylidene)acetate (1.5 g, 8.55 mmol,1.00 equiv, 81%) and CuI (163 mg, 0.86 mmol, 0.10 equiv) in THF (10 mL)maintained under nitrogen was added a solution of chlorotrimethylsilane(1.85 g, 17.03 mmol, 2.00 equiv) in THF (30 mL). The reaction mixturewas stirred at rt for 15 min and then cooled to -15° C. A 1.4 N solutionof methylmagnesium chloride (24.5 mL, 4.00 equiv) in THF was addeddropwise with stirring in 10 min. The resulting solution was stirred at25° C. for 1 h and then quenched by the addition of 20 mL of saturatedaqueous NH₄Cl solution. The mixture was concentrated under vacuum. Theresidue was redissolved in 100 mL of DCM then washed with 1×100 mL ofwater and 2×100 mL of brine. The organic layer was dried over anhydroussodium sulfate and concentrated under vacuum to give 600 mg of crudeethyl 2-(3-methyloxetan-3-yl)acetate as a red oil.

Step 3. 2-(3-Methyloxetan-3-yl)acetic acid

To a solution of ethyl 2-(3-methyloxetan-3-yl)acetate (500 mg, 3.16mmol, 1.00 equiv) in MeOH (15 mL) was added a 2M aqueous sodiumhydroxide (5 mL) solution. The mixture was stirred at 40° C. for 12 hand then cooled to rt. The reaction mixture was concentrated undervacuum. The residue was dissolved in 50 mL of water and then washed with3×50 mL of DCM. The aqueous layer was collected and the pH value of thesolution was adjusted to 5 with 1M HCl. The resulting mixture wasconcentrated under vacuum and the residue was dissolved with 50 mL ofMeOH. The solid material was removed by filtration. The filtrate wasconcentrated under vacuum to give 260 mg of crude2-(3-methyloxetan-3-yl)acetic acid as a red solid. ¹H NMR (400 MHz,D₂O-d₆, ppm): δ 4.63 (s, 2H), 4.33 (s, 2H), 2.19 (s, 2H), 1.27 (s, 3H).

Step 4

A solution of 2-(3-methyloxetan-3-yl)acetic acid (66 mg, 0.51 mmol, 2.00equiv), EDCI (72 mg, 0.38 mmol, 1.50 equiv), HOBt (51 mg, 0.38 mmol,1.50 equiv) and DIPEA (162 mg, 1.25 mmol, 5.00 equiv) in DMF (10 mL) wasstirred at rt for 1 h.N-[6-Azaspiro[2.5]octan-1-ylmethyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamidedihydrochloride (90 mg, 0.25 mmol, 1.00 equiv) was then added and theresulting solution was stirred at 25° C. for 12 h. The reaction mixturewas concentrated under vacuum. The residue was dissolved in 100 mL ofDCM and then washed with 2×100 mL of brine. The organic layer wasconcentrated under vacuum and the residue was purified by Prep-HPLC(SHIMADZU-PDA (LC-08): Column, XSelect CSH Prep C18 OBD Column, 5 um,19*150 mm, mobile phase, water with 0.025% ammonium carbonate and CH₃CN(8% CH₃CN up to 22.0% in 12 min, up to 95.0% in 1 min, hold 95.0% in 1min, down to 8.0% in 2 min); Detector, UV 254/220 nm) to give 13.5 mg(13%) ofN-([6-[2-(3-methyloxetan-3-yl)acetyl]-6-azaspiro[2.5]octan-1-yl]methyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamideas a white solid. LC/MS (Method K, ESI): RT=1.88 min, m/z=397.1 [M+H]⁻.¹H-NMR (400 MHz, CDCl₃, ppm): δ 9.03 (s, 1H), 8.42 (d, 0.1=5.6 Hz, 1H),7.39 (d, J=6.0 Hz, 1H), 6.98 (s, 1H), 6.40 (s, 1H), 4.60-4.59 (m, 2H),4.48-4.46 (m, 2H), 3.99-3.97 (m, 1H), 3.65-3.60 (m, 2H), 3.46˜3.31 (m,3H), 2.73 (s, 2H), 1.76-1.63 (m, 4H), 1.47 (s, 3H), 1.28-1.23 (m, 1H),1.10-1.08 (m, 1H), 0.74-0.72 (m, 1H), 0.42-0.39 (m, 1H).

Example 159N-[[6-(p-tolylcarbamol)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2-carboxamide

A solution ofN-(6-azaspiro[2.5]octan-2-ylmethyl)furo[2,3-c]pyridine-2-carboxamide;2,2,2-trifluoroacetic acid (60 mg, 0.15 mmol, 1.00 equiv),1-isocyanato-4-methyl-benzene (20 mg, 0.15 mmol, 1.00 equiv) andtriethylamine (65 uL, 0.45 mmol, 3.00 equiv) in 10% DMF in DCM (2.0 mL)was stirred at 50° C. for 2 h. The reaction mixture was concentratedunder vacuum and the crude product was purified by Prep-HPLC (Column,Sunfire C18 19×150; mobile phase, CH₃CN:NH₄CO₃/H₂O (10 mmol/L)=5%-85%,10 min; Detector, UV 254 nm) to give 16 mg (25%) ofN-[[6-(p-tolylcarbamoyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2-carboxamideas an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (s, 1H),9.05-9.00 (m, 1H), 8.47 (d, J=5.3 Hz, 1H), 8.33 (s, 1H), 7.82 (d, J=5.2,1.0 Hz, 11), 7.61 (s, 1H), 7.31 (d, 2H), 7.01 (d, J=8.2 Hz, 2H),3.67-3.53 (m, 2H), 3.46-3.25 (m, 21H), 2.21 (s, 3H), 1.70-1.58 (m, 1H),1.50-1.37 (m, 2H), 1.24-1.14 (m, 1H), 1.12-0.98 (m, 1H), 0.60-0.52 (m,1H), 0.31 (t, J=4.8 Hz, 1H).

Example 174N-([6-[2-(3-hydroxy-3-methylcyclobutyl)acetyl]-6-azaspiro[2.5]octan-1-yl]methyl)furo[2,3-c]pyridine-2-carboxamide

Step 1. tert-Butyl 2-(2,2-dichloro-3-oxocyclobutyl)acetate

A mixture of tert-butyl but-3-enoate (10 g, 70.33 mmol, 1.00 equiv) inether (250 mL), trichloroacetyl chloride (34 g, 186.98 mmol, 2.66 equiv)and Zn—Cu (13 g) in ethylene glycol dimethyl ether (40 mL) was stirredunder nitrogen at rt for 48 h. The reaction mixture was filtered toremove the solid material. The filtrate was concentrated under vacuumand the residue was purified on a silica gel column eluted with ethylacetate/petroleum ether (1:10) to yield 21 g of tert-butyl2-(2,2-dichloro-3-oxocyclobutyl)acetate as a brown liquid. TLC:petroleum ether:ethyl acetate=2:1, R_(f)=0.6.

Step 2. tert-Butyl 2-(3-oxocyclobutyl)acetate

A mixture of tert-butyl 2-(2,2-dichloro-3-oxocyclobutyl)acetate (500 mg,1.98 mmol, 1.00 equiv) and zinc (635 mg, 9.71 mmol, 4.91 equiv) in asaturated NH₄Cl solution in MeOH (20 mL) was stirred at rt overnight.The mixture was filtered to remove the solid material. The filtrate wasconcentrated under vacuum to give 300 mg (82%) of tert-butyl2-(3-oxocyclobutyl)acetate as a light yellow oil. TLC: petroleumether:ethyl acetate=2:1, R_(f)=0.5.

Step 3. tert-Butyl 2-(3-hydroxy-3-methylcyclobutyl)acetate

To a stirred solution of tert-butyl 2-(3-oxocyclobutyl)acetate (300 mg,1.63 mmol, 1.00 equiv) in THF (50 mL) maintained under nitrogen at 0° C.was added dropwise a 3M solution of CH₃MgBr (0.8 mL) in THF. Thereaction mixture was stirred at rt for 1 h and then quenched by theaddition of 20 mL of saturated NH₄Cl solution. The organic layer wascollected and the aqueous layer was extracted with 50 mL of DCM. Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to give 270 mg (83%) oftert-butyl 2-(3-hydroxy-3-methylcyclobutyl)acetate as a light yellowoil.

Step 4. 2-(3-Hydroxy-3-methylcyclobutyl)acetic acid

To a solution of tert-butyl 2-(3-hydroxy-3-methylcyclobutyl)acetate (270mg, 1.35 mmol, 1.00 equiv) in DCM (50 mL) was added TFA (1 mL). Theresulting solution was stirred overnight at room temperature thenconcentrated under vacuum to give 240 mg of crude2-(3-hydroxy-3-methylcyclobutyl)acetic acid as brown oil.

Step 5

A solution of 2-(3-hydroxy-3-methylcyclobutyl)acetic acid (200 mg, 1.39mmol, 5.58 equiv), EDCI (265 mg, 1.38 mmol, 5.56 equiv), HOBt (187 mg,1.38 mmol, 5.57 equiv) and DIPEA (1 mL) in DMF (10 mL) was stirred for10 min at rt.N-[6-Azaspiro[2.5]octan-1-ylmethyl]furo[2,3-c]pyridine-2-carboxamidehydrochloride (80 mg, 0.25 mmol, 1.00 equiv) was then added. Thereaction mixture was stirred overnight at rt and then concentrated undervacuum. The residue was dissolved in 100 mL of DCM and the resultingsolution was washed with 50 mL of H₂O. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified on a silica gel column eluted with DCM/MeOH (20:1).The partially purified product (110 mg) was repurified by Prep-HPLC(Column, Xbridge RP18 19*150; mobile phase, CH₃CN:NHCO₃/H₂O (10 mmol/L),5%-19% over 15 min; Detector, UV 254 nm) to give 19.6 mg (19%) ofN-([6-[2-(3-hydroxy-3-methylcyclobutyl)acetyl]-6-azaspiro[2.5]octan-1-yl]methyl)furo[2,3-c]pyridine-2-carboxamideas a white solid. LC/MS (Method I, ESI): RT=1.66 min, m z=412.0 [M+H]⁺.¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 9.06 (t, 2H), 8.48 (d, J=5.21 Hz, 2H),7.81 (d, J=4.4 Hz, 1H). 7.61 (s, 1H), 4.75 (s, 1H), 3.73-3.53 (m, 1H),3.49-3.32 (m, 1H), 2.50-2.21 (m, 3H), 2.03-2.02 (m, 3H), 1.64 (s, 3H),1.44-1.33 (m, 2H), 1.19-1.13 (m, 3H), 1.10-1.03 (m, 1H), 0.56-0.53 (m,1H), 0.32-0.29 (m, 1H).

Example 274 tert-Butyl2-[(4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-carbonylamino)methyl]-6-azaspiro[2.5]octane-6-carboxylate

Step 1. tert-Butyl1-[[(4-nitrophenoxycarbonyl)amino]methyl]-6-azaspiro[2.5]octane-6-carboxylate

To a stirred mixture of tert-butyl1-(aminomethyl)-6-azaspiro[2.5]octane-6-carboxylate oxalic acid salt(200 mg, 0.61 mmol, 1.00 equiv) and 4-nitrophenyl chloroformate (122 mg,0.61 mmol, 1.00 equiv) in DCM (10 mL) at 0-5° C. was added triethylamine(184 mg, 1.82 mmol, 3.00 equiv) dropwise. The resulting solution wasstirred at 0-5° C. for another 2 h. The resulting mixture wasconcentrated under vacuum to give 400 mg of crude tert-butyl1-[[(4-nitrophenoxycarbonyl)amino]methyl]-6-azaspiro[2.5]octane-6-carboxylateas a yellow solid. TLC: petroleum ether:ethyl acetate=2:1, R_(f)=0.3.

Step 2

A solution of tert-butyl1-[[(4-nitrophenoxycarbonyl)amino]methyl]-6-azaspiro[2.5]octane-6-carboxylate(250 mg, 0.62 mmol, 1.00 equiv), 1H,4H,5H,6H-pyrrolo[3,4-c]pyrazolehydrochloride (90 mg, 0.62 mmol, 1.00 equiv) and triethylamine (187 mg,1.85 mmol, 3.00 equiv) in ethanol (5 mL) was stirred at 78° C. for 2 h.The resulting mixture was warmed to rt and concentrated under vacuum.The residue was dissolved in 50 mL of DCM and the resulting mixture waswashed with 3×50 mL of brine. The organic layer was concentrated undervacuum and the residue was purified by Prep-HPLC (Waters-1; Column,Sunfire C18 19*150; mobile phase A: 0.2% aqueous NH₄HCO₃, phase B:CH₃CN, gradient: 10% to 43% B over 10 min, up to 100% B in 13 min,Detector, UV 254 nm) to give 33.7 mg (15%) of tert-butyl1-[[([1H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-5-yl]carbonyl)amino]methyl]-6-azaspiro[2.5]octane-6-carboxylateas a white solid. LC/MS (Method Q. ESI): RT=1.49 min, m z=376.2 [M+H]⁺.¹H-NMR (300 MHz, CDCl₃, ppm): δ 7.36 (s, 1H), 4.51 (s, 4H), 4.31 (s,1H), 3.61 (br s, 2H), 3.34-3.22 (m, 4H), 1.67-1.60 (m, 1H), 1.49 (s,1H), 1.46 (s, 9H), 1.39 (s, 1H), 1.18-1.14 (m, 1H), 0.97-0.92 (m, 1H),0.60-0.57 (m, 1H), 0.29-0.21 (m, 1H).

Example 275N-([6-[2-(1,4-dimethylpiperidin-4-yl)acetyl]-6-azaspiro[2.5]octan-1-yl]methyl)furo[2,3-c]pyridine-2-carboxamide

Step 1. Ethyl 2-(1-methylpiperidin-4-ylidene)acetate

A mixture of 1-methylpiperidin-4-one (5 g, 44.19 mmol, 1.00 equiv) and(ethoxycarbonylmethylene)triphenylphosphorane (17 g, 48.80 mmol, 1.00equiv) in DCM (200 mL) was stirred at 0-5° C. for 3 h. The resultingmixture was concentrated under vacuum. The residue was purified on asilica gel column eluted with ethyl acetate/petroleum ether (1:10) togive 1 g (12%) of ethyl 2-(1-methylpiperidin-4-ylidene)acetate as acolorless oil. LC/MS (Method Q, ESI): RT=0.35 min, m z=184.0 [M+H]⁺.

Step 2. Ethyl 2-(1,4-dimethylpiperidin-4-yl)acetate

A solution of ethyl 2-(1-methylpiperidin-4-ylidene)acetate (1 g, 5.46mmol, 1.00 equiv), CuI (1.2 g, 6.30 mmol, 1.15 equiv) and (CH₃)₃SiCl(2.3 g, 21.3 mmol, 3.90 equiv) in THF (50 mL) was stirred under nitrogenat rt for 2 h. The reaction mixture was cooled to −30° C. and a 3Msolution of MeMgBr (11 mL, 33.0 mmol, 6.04 equiv) in THF was addeddropwise with stirring. The reaction mixture was stirred at −30° C. for30 min and then slowly warmed to rt and then stirred overnight. Thereaction was quenched by the addition of 50 mL of water and theresulting solution was extracted with 4×50 mL of ethyl acetate. Thecombined organic layers was dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to give 800 mg of crude ethyl2-(1,4-dimethylpiperidin-4-yl)acetate as a light yellow oil. LC/MS(Method Q, ESI): RT=0.26 min, m z=200.0 [M+H]⁺.

Step 3. 2-(1,4-Dimethylpiperidin-4-yl)acetic acid

To a solution of ethyl 2-(1,4-dimethylpiperidin-4-yl)acetate (800 mg,4.01 mmol, 1.00 equiv) in THF (10 mL) was added a 10% aqueous sodiumhydroxide solution (6 mL). The resulting solution was stirred overnightat 65° C. The reaction mixture was cooled to rt and the pH value of thesolution was adjusted to 7 with 5% HCl. The resulting mixture wasextracted with 3×50 mL of DCM. The combined organic layers was driedover anhydrous sodium sulfate and concentrated under vacuum to give 1.6g of crude 2-(1,4-dimethylpiperidin-4-yl)acetic acid as a light yellowsolid. LC/MS (Method R, ESI): RT—0.26 min, m z=172.0 [M+H]⁺.

Step 4. tert-Butyl1-([furo[2,3-c]pyridin-2-ylformamido]methyl)-6-azaspiro[2.5]octane-6-carboxylate

A solution of furo[2,3-c]pyridine-2-carboxylic acid (510 mg, 3.13 mmol,1.50 equiv), EDCI (517 mg, 2.70 mmol, 1.30 equiv), HOBt (365 mg, 2.70mmol, 1.30 equiv) and DIPEA (2 mL) in DMF (20 mL) was stirred at rt for10 min. tert-Butyl 1-(aminomethyl)-6-azaspiro[2.5]octane-6-carboxylate(500 mg, 2.08 mmol, 1.00 equiv) was then added and the resultingsolution was stirred overnight at rt. The reaction mixture was dilutedwith 200 mL of ethyl acetate and washed with 100 mL of H₂O. The organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified on a silica gel column elutedwith ethyl acetate/petroleum ether (1:1) to give 600 mg (75%) oftert-butyl1-([furo[2,3-c]pyridin-2-ylformamido]methyl)-6-azaspiro[2.5]octane-6-carboxylateas a light yellow oil. LC/MS (Method J, ESI): RT=1.23 min, m z=386.0[M+H]⁺.

Step 5.N-[6-Azaspiro[2.5]octan-1-ylmethyl]furo[2,3-c]pyridine-2-carboxamidehydrochloride

A solution of tert-butyl1-([furo[2,3-c]pyridin-2-ylformamido]methyl)-6-azaspiro[2.5]octane-6-carboxylate(1 g, 2.59 mmol, 1.00 equiv) in 1M solution of hydrogen chloride in MeOH(100 mL) was stirred at rt for 3 h. The reaction mixture wasconcentrated under vacuum to give 0.8 g (96%) ofN-[6-azaspiro[2.5]octan-1-ylmethyl]furo[2,3-c]pyridine-2-carboxamidehydrochloride as a white solid. LC/MS (Method Q, ESI): RT=0.38 min,m/z=286.0[M+H]⁺.

Step 6

A solution of 2-(1,4-dimethylpiperidin-4-yl)acetic acid (1.6 g (crudesolid), 9.34 mmol, 11.16 equiv), EDCI (300 mg, 1.56 mmol, 1.87 equiv),HOBt (250 mg, 1.85 mmol, 2.21 equiv) and DIPEA (2 mL) in DMF (30 mL) wasstirred at rt for 10 min.N-[6-Azaspiro[2.5]octan-1-ylmethyl]furo[2,3-c]pyridine-2-carboxamidedihydrochloride (300 mg, 0.84 mmol, 1.00 equiv) was then added and theresulting solution was stirred overnight at rt. The solid material wasremoved by filtration. The filtrate was concentrated under reducedpressure and the residue was purified by Prep-HPLC (Column: Sunfire C1819*150: mobile phase, CH₃CN:NH₄CO₃/H₂O (10 mmol/L), 15%-60%, 10 min;Detector, UV 254 nm) to give 43 mg (12%) ofN-([6-[2-(1,4-dimethylpiperidin-4-yl)acetyl]-6-azaspiro[2.5]octan-1-yl]methyl)furo[2,3-c]pyridine-2-carboxamideas a light yellow solid. LC/MS (Method A, ESI): RT=1.70 min, m z=439.0[M+H]⁻. ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 9.04 (s, 2H), 8.48 (d, J=5.1Hz, 1H), 7.80 (d, J=5.4 Hz, 1H), 7.60 (s, 1H), 3.67-3.56 (m, 2H),3.39-3.32 (m, 2H), 2.29-2.24 (m, 5H), 2.11-2.09 (m, 6H), 1.59-1.52 (m,3H), 1.50-1.22 (m, 4H), 1.21-1.16 (m, 1H), 1.06-1.01 (m, 1H), 0.94 (d,J=5.4 Hz, 3H), 0.60-0.50 (m, 1H), 0.31-0.29 (m, 1H).

Example 339N-[[6-[4-(4-Methylpiperazin-1-yl)benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2-carboxamide

Step 1. Ethyl 4-(4-methylpiperazin-1-yl)benzoate

A solution of ethyl 4-fluorobenzoate (2 g, 11.89 mmol, 1.00 equiv),1-methylpiperazine (1.6 g, 15.97 mmol, 1.34 equiv) and potassiumcarbonate (2.2 g, 15.92 mmol, 1.34 equiv) in DMF (30 mL) was stirred at80° C. for 2 days. The resulting solution was diluted with 150 mL of H₂Oand the pH value of the solution was adjusted to 1 with 10% HCl. Theresulting solution was washed with 100 mL of ethyl acetate. The aqueouslayer was collected and the pH value of the solution was adjusted to 10with sodium carbonate. The resulting solution was extracted with 2×100mL of ethyl acetate. The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under vacuum to give1.3 g (44%) of ethyl 4-(4-methylpiperazin-1-yl)benzoate as a whitesolid. TLC: DCM:MeOH=10:1, R_(f)=0.5.

Step 2. 4-(4-Methylpiperazin-1-yl)benzoic acid

To a solution of ethyl 4-(4-methylpiperazin-1-yl)benzoate (1.3 g, 5.24mmol, 1.00 equiv) in THF (10 mL) was added a 10% aqueous sodiumhydroxide solution (8 mL). The resulting solution was stirred at 70° C.overnight. After cooling to rt, the pH value of the solution wasadjusted to 5 with 5% HCl. The resulting solution was extracted with3×100 mL of DCM. The combined organic layers was and concentrated undervacuum to give 2.2 g of crude 4-(4-methylpiperazin-1-yl)benzoic acid asa white solid. LC/MS (Method C, ESI): RT=0.54 min, m/z=221 [M+H]⁺.

Step 3.N-[6-[[4-(4-Methylpiperazin-1yl)phenyl]carbonyl]-6-azaspiro[2.5]octan-1-yl)methyl]furo[2,3-c]pyridine-2-carboxamide

A solution of 4-(4-methylpiperazin-1-yl)benzoic acid (200 mg, 0.91 mmol,1.00 equiv), EDCI (200 mg, 1.04 mmol, 1.15 equiv), HOBt (150 mg, 1.11mmol, 1.22 equiv) and DIPEA (2 mL) in DMF (10 mL) was stirred at rt for10 min.N-[6-Azaspiro[2.5]octan-1-ylmethyl]furo[2,3-c]pyridine-2-carboxamidedihydrochloride (100 mg, 0.28 mmol, 0.31 equiv) was then added and theresulting solution was stirred at rt overnight. The reaction mixture wasconcentrated under vacuum and the crude product was purified byPrep-HPLC (Column, Sunfire C18 19×150; mobile phase, CH₃CN: NH₄CO/H₂O(10 mmol/L)=15%-60%, 10 min; Detector, UV 254 nm) to give 40 mg (9%) ofN-[(6-[[4-(4-methylpiperazin-1-yl)phenyl]carbonyl]-6-azaspiro[2.5]octan-1-yl)methyl]furo[2,3-c]pyridine-2-carboxamideas an off-white solid. LC/MS (Method F, ESI): RT=1.12 min, mz=488.3[M+H]⁻. ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 9.07-9.05 (m, 2H), 8.48(d, J=5.4 Hz, 1H), 7.82-7.80 (m, 1H), 7.61 (s, 1H), 7.26 (d, J=8.7 Hz,2H), 6.94 (d, J=8.7 Hz, 2H), 3.62-3.58 (m, 2H), 3.39-3.25 (m, 3H),3.25-3.17 (m, 4H), 2.49-2.41 (m, 4H), 2.21 (s, 3H), 1.68-1.62 (m, 1H),1.46-1.43 (m, 2H), 1.23-1.18 (m, 1H), 1.04-1.00 (m, 1H), 0.58-0.56 (m,1H), 0.35-0.29 (m, 1H).

Example 383 tert-Butyl2-[(pyrazolo[1,5-b]pyridazine-5-carbonylamino)methyl]-6-azaspiro[2.5]octane-6-carboxylate

A solution of lithium pyrazolo[1,5-b]pyridazine-5-carboxylate (90 mg,0.53 mmol, 1.00 equiv), tert-butyl1-(aminomethyl)-6-azaspiro[2.5]octane-6-carboxylate trifluoroacetic acidsalt (193 mg, 0.54 mmol, 1.01 equiv), EDCI (372 mg, 1.94 mmol, 3.66equiv), HOBt (99 mg, 0.73 mmol, 1.38 equiv) and triethylamine (246 mg,2.43 mmol, 4.6 equiv) in DMF (5 mL) was stirred at rt for 3 h. Thereaction was then quenched by the addition of 100 mL of H₂O and theresulting solution was extracted with 3×100 mL of ethyl acetate. Thecombined organic layers were washed with 3×100 mL of brine, dried oversodium sulfate and concentrated under vacuum. The residue was firstpurified on a silica gel column eluted with DCM:MeOH (30:1). Thepartially purified product was repurified by Prep-HPLC (Waters-1;Column, XBridge C18 19*150; mobile phase A: 0.2% aqueous NH₄HCO₃; mobilephase B: CH₃CN; gradient, 10 to 43% CH₃CN in 10 min, up to 100% in 13min; Detector, UV 254 nm) to give 17.2 mg (9%) of tert-butyl1-([pyrazolo[1,5-b]pyridazin-3-ylformamido]methyl)-6-azaspiro[2.5]octane-6-carboxylateas a white solid. LC/MS (Method S, ESI): RT=1.48 min, m/z=386.0 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆, ppm): δ 8.77 (t, J=2.4 Hz, 1H), 8.74 (s, 1H),8.73 (s, 1H), 8.18 (d, J=2.4 Hz, 1H), 7.05 (d, J=2.7 Hz, 1H), 3.59-3.43(m, 2H), 3.41-3.35 (m, 2H), 3.25-3.17 (m, 2H), 1.67-1.54 (m, 1H),1.46-1.31 (m, 11H), 1.19-1.09 (m, 1H), 1.05-0.95 (m, 1H), 0.59-0.50 (m,1H), 0.31-0.25 (m, 1H).

Example 394N-[[6-[2-(6-Amino-3-pyridyl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide

A solution of 2-(6-aminopyridin-3-yl)acetic acid (150 mg, 0.99 mmol,1.00 equiv),N-6-azaspiro[2.5]octan-1-ylmethyl-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamide(350 mg, 1.22 mmol, 1.20 equiv), DIPEA (400 mg, 3.00 equiv), EDCI (230g, 1.20 mol, 1.20 equiv) and HOBt (170 mg, 1.26 mmol, 1.20 equiv) in DMF(20 mL) was stirred at rt for 20 h. The resulting mixture wasconcentrated under vacuum and the residue was first purified on a silicagel column eluted with DCM/MeOH (5:1). The partially purified product(300 mg) was repurified by Flash-Prep-HPLC (IntelFlash-1: Column, silicagel; mobile phase, 15 to 45% CH₃CN in within 30 min; Detector, UV 254nm) to give 93 mg (22%) ofN-([6-[2-(6-aminopyridin-3-yl)acetyl]-6-azaspiro[2.5]octan-1-yl]methyl)-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamideas an off-white solid. LC/MS (Method C, ESI): RT=1.01 min, m z=421.1[M+H]⁻. ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 8.57 (s, 1H), 8.47 (d, J=4.8Hz, 1H), 7.74 (s, 1H), 7.39 (d, J=4.8 Hz, 1H), 7.21 (dd, J=6.0 Hz, 2.4Hz, 1H), 6.44-6.36 (m, 2H), 5.72 (s, 2H), 4.62 (d, J=2.7 Hz, 4H),3.65-3.54 (m, 4H), 3.40-3.33 (m, 1H), 3.18-3.09 (m, 3H), 1.54-1.48 (m,11H), 1.32-0.95 (m, 4H), 0.55-0.45 (m, 1H), 0.25-0.15 (m, 1H).

Example 399N-[[6-[2-(4-Methyltetrahydropyran-4-yl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide

Step 1. Ethyl 2-(oxan-4-ylidene)acetate

A solution of oxan-4-one (2 g, 19.98 mmol, 1.00 equiv) and(ethoxycarbonylmethylene)triphenylphosphorane (8 g, 22.96 mmol, 1.15equiv) in acetonitrile (50 mL) was stirred at 70° C. for 16 h. Theresulting mixture was cooled to rt and concentrated. The residue waspurified on a silica gel column eluted with ethyl acetate/petroleumether (1:5) to give 1.9 g (56%) of ethyl 2-(oxan-4-ylidene)acetate as acolorless solid. TLC: petroleum ether:ethyl acetate=1:2, R_(f)=0.5.

Step 2. Ethyl 2-(4-methyloxan-4-yl)acetate

To a stirred solution of CuI (2.9 g, 15.23 mmol, 3.24 equiv) in ether(50 mL) maintained under nitrogen at 0° C. was added a 1.6 M solution ofmethyllithium (20 mL, 32 mmol, 6.8 equiv) in ether dropwise. Theresulting solution was stirred at 0° C. for 10 min and the ether solventwas removed from the reaction vessel under vacuum at 0° C. DCM (50 mL)was then added to the residue and the reaction was cooled to −78° C.Chlorotrimethylsilane (1.9 g, 17.6 mmol, 3.7 equiv) was then addeddropwise followed by a solution of ethyl 2-(oxan-4-ylidene)acetate (800mg, 4.70 mmol, 1.00 equiv) in DCM (20 mL) to the reaction mixture at−78° C. The resulting solution was stirred for another 30 min at −78° C.and then at 0° C. for 2 h. The reaction quenched by the addition of 50mL of water. The organic layer was dried over anhydrous sodium sulfateand concentrated under vacuum to give 750 mg (86%) of ethyl2-(4-methyloxan-4-yl)acetate as a colorless oil.

Step 3. 2-(4-Methyloxan-4-yl)acetic acid

To a solution of ethyl 2-(4-methyloxan-4-yl)acetate (750 mg, 4.03 mmol,1.00 equiv) in ethanol (20 mL) at 0° C. was added dropwise a solution ofsodium hydroxide (817 mg, 5.00 equiv) in water (4 mL) with stirring. Theresulting solution was stirred overnight at rt and then concentrated toremove ethanol. The resulting solution was diluted with 10 mL of H₂O andwashed with 3×20 mL of ether. The aqueous layer was collected and the pHvalue of the solution was adjusted to 4-5 with 2N HCl. The aqueous layerwas extracted with 4×15 mL of ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentrated togive 600 mg (94%) of 2-(4-methyloxan-4-yl)acetic acid as yellow oil.LC/MS (Method S, ESI): RT=0.5 min, m/z=159 [M+H]⁺.

Step 4

A solution of 2-(4-methyloxan-4-yl)acetic acid (100 mg, 0.63 mmol, 1.26equiv), DIPEA (1 mL), HOBt (85 mg, 0.63 mmol, 1.26 equiv), and EDCI (120mg, 0.63 mmol, 1.25 equiv) in DMF (4 mL) was stirred at rt for 10 min.N-[6-Azaspiro[2.5]octan-1-ylmethyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamidedihydrochloride (180 mg, 0.50 mmol, 1.00 equiv) was then added and thereaction mixture was stirred overnight at rt. The resulting solution wasdiluted with 100 mL of DCM and then washed with 60 mL of H₂O. Theorganic layer was dried over anhydrous sodium sulfate and concentrated.The residue was purified on a silica gel column eluted with DCM/MeOH(20:1) to give 110 mg (51%) ofN-([6-[2-(4-methyloxan-4-yl)acetyl]-6-azaspiro[2.5]octan-1-yl]methyl)-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamideas a light yellow solid. LC/MS (Method F, ESI): RT=1.19 min, m/z=428.0[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 8.55 (s, 1H). 8.46 (d, J=5.1Hz, 1H), 7.38 (d, J=5.1 Hz, 1H), 6.42 (t, J=4.9 Hz, 1H), 4.61 (d, 4H),3.69-3.31 (m, 8H), 3.15-3.08 (m, 2H), 2.31 (s, 2H), 1.62-1.49 (m, 3H),1.45-1.25 (m, 4H), 1.21-1.05 (m, 1H), 1.04-0.89 (m, 4H), 0.55-0.51 (m,1H), 0.25-0.15 (m, 1H).

Example 403N-[[6-[2-[4-Methyl-1-(2,2,2-trifluoroethyl)-4-piperidyl]acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide

Step 1. tert-Butyl4-methyl-4-[2-oxo-2-(1-[[([1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]carbonyl)amino]methyl]-6-azaspiro[2.5]octan-6-yl)ethyl]piperidine-1-carboxylate

A solution of 2-[1-[(tert-butoxy)carbonyl]-4-methylpiperidin-4-yl]aceticacid (450 mg, 1.75 mmol, 2.09 equiv), EDCI (340 mg), HOBt (250 mg, 1.85mmol, 2.22 equiv) and DIPEA (2 mL) in DMF (15 mL) was stirred at rt for10 min.N-[6-Azaspiro[2.5]octan-1-ylmethyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamidedihydrochloride (300 mg, 0.83 mmol, 1.00 equiv) was then added and thereaction mixture was stirred overnight at rt. The resulting solution wasdiluted with 200 mL of ethyl acetate and washed with 100 mL of H₂O. Theorganic layer was dried over anhydrous sodium sulfate and concentrated.The residue was purified on a silica gel column eluted with DCM/MeOH(20:1) to yield 210 mg (48%) of tert-butyl4-methyl-4-[2-oxo-2-(1-[[([1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]carbonyl)amino]methyl]-6-azaspiro[2.5]octan-6-yl)ethyl]piperidine-1-carboxylateas a light yellow oil. TLC: DCM:MeOH=10:1, R_(f)=0.5.

Step 2.N-([6-[2-(4-Methylpiperidin-4-yl)acetyl]-6-azaspiro[2.5]octan-1-yl]methyl)-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamidehydrochloride

Hydrogen chloride gas was bubbled into a solution of tert-butyl4-methyl-4-[2-oxo-2-(1-[[([1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]carbonyl)amino]methyl]-6-azaspiro[2.5]octan-6-yl)ethyl]piperidine-1-carboxylate(210 mg, 0.40 mmol, 1.00 equiv) in 1,4-dioxane (20 mL) at 0° C. for 20min. The resulting solution was stirred at rt for 1 h and thenconcentrated under vacuum to give 220 mg of crudeN-([6-[2-(4-methylpiperidin-4-yl)acetyl]-6-azaspiro[2.5]octan-1-yl]methyl)-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamidehydrochloride as a light yellow solid. LC/MS (Method F, ESI): RT=0.89min, m/z=426.0[M+H]⁺

Step 3

To a solution ofN-([6-[2-(4-methylpiperidin-4-yl)acetyl]-6-azaspiro[2.5]octan-1-yl]methyl)-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamidedihydrochloride (220 mg, 0.44 mmol, 1.00 equiv) in DMF (10 mL) at rt wasadded 2,2,2-trifluoroethyl trifluoromethanesulfonate (140 mg, 0.60 mmol,1.37 equiv) followed by DIPEA (2 mL). The reaction mixture was stirredat room temperature for 2 h and then diluted with 200 mL of ethylacetate. The resulting mixture was washed with 100 mL of H₂O. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified on a silica gelcolumn eluted with dichloromethane/methanol (20:1) to give 35.2 mg (16%)ofN-[(6-[2-[4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl]acetyl]-6-azaspiro[2.5]octan-1-yl)methyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamideas a white solid. LC/MS (Method I, ESI): RT=1.15 min, m z=508.0 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆, ppm): δ 8.56 (s, 1H), 8.46 (d, J=4.5 Hz, 1H),7.39 (d, J=4.8 Hz, 1H), 6.43 (s, 1H), 4.62 (s, 4H), 3.65-3.58 (m, 2H),3.48-3.33 (m, 3H), 3.20-3.01 (m, 4H), 2.59-2.50 (m, 3H), 2.27 (s, 2H),1.59-1.56 (m, 3H), 1.39-1.30 (m, 3H), 1.01-0.96 (m, 4H), 0.49-0.45 (m,1H), 0.25-0.23 (m, 1H).

Example 405N-[[6-[4-(1-Methyl-4-piperidyl)benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide

Step 1. tert-Butyl4-[4-(ethoxycarbonyl)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate

A mixture of ethyl 4-bromobenzoate (1 g, 4.37 mmol, 1.00 equiv),tert-butyl4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate(1.4 g, 4.53 mmol, 1.04 equiv), Pd(PPh₃)₄ (0.2 g), and potassiumcarbonate (800 mg, 5.79 mmol, 1.33 equiv) in 1,4-dioxane (10 mL) wasstirred under nitrogen in a 20-mL sealed tube at 100° C. overnight. Thereaction mixture was cooled to rt then diluted with 120 mL of ethylacetate. The solid material was removed by filtration and the filtratewas washed with 100 mL of water. The organic layer was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified on a silica gel column eluted with ethyl acetate/petroleumether (1:20) to give 1 g (69%) of tert-butyl4-[4-(ethoxycarbonyl)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate asa white solid TLC: petroleum ether:ethyl acetate=5:1, R_(f)=0.3.

Step 2. tert-Butyl 4-[4-(ethoxycarbonyl)phenyl]piperidine-1-carboxylate

A mixture of tert-butyl4-[4-(ethoxycarbonyl)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (1g, 3.02 mmol, 1.00 equiv) and 10% palladium on carbon (0.5 g) catalystin ethanol (50 mL) was stirred under 1 atmosphere of H₂ at rt for 2 h.The catalyst was removed by filtration. The filtrate was concentratedunder vacuum to give 1.2 g of crude tert-butyl4-[4-(ethoxycarbonyl)phenyl]piperidine-1-carboxylate as a gray coloredoil. TLC: petroleum ether:ethyl acetate=5:1, R_(f)=0.4.

Step 3. Ethyl 4-(piperidin-4-yl)benzoate hydrochloride

Thionyl chloride (2 mL) was added dropwise with stirring at rt toethanol (50 mL). tert-Butyl4-[4-(ethoxycarbonyl)phenyl]piperidine-1-carboxylate (1 g, 3.00 mmol,1.00 equiv) was then added to the reaction mixture and the resultingsolution was stirred at rt for 1 h. The reaction mixture wasconcentrated under vacuum to give 0.8 g (99%) of ethyl4-(piperidin-4-yl)benzoate hydrochloride as an off-white solid. LC/MS(Method Q, ESI): RT=1.03 min, m/z=233 [M−H]⁺.

Step 4. Methyl 4-(1-methylpiperidin-4-yl)benzoate

A solution of methyl 4-(piperidin-4-yl)benzoate hydrochloride (800 mg,3.13 mmol, 1.00 equiv) and paraformaldehyde (180 mg) in ethanol (50 mL)and water (10 mL) was stirred at 60° C. for 1 h. Sodium cyanoborohydride(400 mg) and acetic acid (0.1 mL) were then added. The resultingsolution was stirred overnight at 60° C. The reaction mixture was cooledto rt and concentrated under vacuum. The resulting solution was dilutedwith 50 mL of H₂O and extracted with 3×50 mL of DCM. The combinedorganic layers were dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified on a silica gel column elutedwith DCM/MeOH (10:1) to give 700 mg (96%) of methyl4-(1-methylpiperidin-4-yl)benzoate as a colorless oil. LC/MS (Method I,ESI): RT=1.12 min, m z=247 [M+H]⁻.

Step 5. 4-(1-Methylpiperidin-4-yl)benzoic acid

To a solution of ethyl 4-(1-methylpiperidin-4-yl)benzoate (700 mg, 2.83mmol, 1.00 equiv) in ethanol (30 mL) was added a solution of sodiumhydroxide (340 mg, 8.50 mmol, 3.00 equiv) in water (5 mL). The reactionmixture was stirred overnight at 60° C. and then cooled tort. The pH ofthe solution was adjusted to 7 with 5% HCl and then extracted with 3×50mL of DCM. The combined organic layers were dried over anhydrous sodiumsulfate then concentrated under vacuum to give 1 g of crude4-(1-methylpiperidin-4-yl)benzoic acid as a white solid. LC/MS (MethodI, ESI): RT=0.93 min, m z=220 [M+H]⁺.

Step 6

A solution of 4-(1-methylpiperidin-4-yl)benzoic acid (131 mg, 0.60 mmol,2.15 equiv), EDCI (80 mg, 0.42 mmol, 1.50 equiv), HOBt (57 mg, 0.42mmol, 1.52 equiv) and DIPEA (1 mL) in DMF (6 mL) was stirred at rt for10 min.N-[6-Azaspiro[2.5]octan-1-ylmethyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamidedihydrochloride (100 mg, 0.28 mmol, 1.00 equiv) was then added and thereaction mixture was stirred overnight at rt. The resulting solution wasdiluted with 30 mL of H₂O then extracted with 3×50 mL of DCM. Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude product was purified by Prep-HPLC(Column, Sunfire C18 19*150; mobile phase, CH₃CN:NH₃/H₂O (5 mL/10 L),15%-70%, 10 min; Detector, UV 254 nm) to give 23.7 mg (17%) ofN-[(6-[[4-(1-methylpiperidin-4-yl)phenyl]carbonyl]-6-azaspiro[2.5]octan-1-yl)methyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamideas a white solid LC/MS (Method I, ESI): RT=1.25 min, m z=488.0 [M+H]⁻.¹H NMR (300 MHz, DMSO-d₆, ppm): δ 8.56 (s, 1H), 8.46 (d, J=4.5 Hz, 1H),7.38 (d, J=3.6 Hz, 1H), 7.29 (s, 4H), 6.43 (s, 1H), 4.63 (s, 4H),3.76-3.74 (m, 1H), 3.51-3.33 (m, 3H), 3.20-3.12 (m, 2H), 2.83 (d, J=5.1Hz, 2H), 2.44-2.39 (m, 1H), 2.18 (s, 3H), 1.98-1.91 (m, 2H), 1.70-1.62(m, 5H), 1.54-1.24 (m, 3H), 1.01-0.96 (m, 1H), 0.54-0.49 (m, 1H),0.24-0.21 (m, 1H).

Example 406 tert-Butyl2-[[(6-amino-1,3-dihydropyrrolo[3,4-c]pyridine-2-carbonyl)amino]methyl]-6-azaspiro2.5 octane-6-carboxylate

A solution of tert-butyl1-[[(4-nitrophenoxycarbonyl)amino]methyl]-6-azaspiro[2.5]octane-6-carboxylate(200 nag, 0.49 mmol, 1.00 equiv), 1H,2H,3H-pyrrolo[3,4-c]pyridin-6-amine(80 mg, 0.59 mmol, 1.20 equiv) and DIPEA (200 mg, 1.55 mmol, 3.14 equiv)in DCM (50 mL) was stirred at rt for 2 h. The reaction mixture wasconcentrated under vacuum. The residue was purified on a silica gelcolumn eluted with ethyl acetate/petroleum ether (5:1) to give 0.113 g(57%) of tert-butyl1-[[([6-amino-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]carbonyl)amino]methyl]-6-azaspiro[2.5]octane-6-carboxylateas a light yellow solid. LC/MS (Method K, ESI): RT=1.65 min, m z=402.2[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 7.94 (s, 1H), 6.59 (s, 1H),5.25 (s, 2H), 4.64-4.52 (m, 6H), 3.61 (s, 2H), 3.27 (d, J 8.1 Hz, 5H),1.65 (d, J=8.4 Hz, 1H), 7.94 (s, 9H), 1.14-1.09 (m, 1H), 0.95-0.83 (m,1H), 0.59-0.55 (m, 1H), 0.26-0.24 (m, 1H).

Example 409 (3-Methyloxetan-3-yl)2-[[(1,1,3,3-tetradeuteriopyrrolo[3,4-c]pyridine-2-carbonyl)amino]methyl]-6-azaspiro[2.5]octane-6-carboxylate

Step 1. tert-Butyl1-[({1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl}carbonylamino)methyl]-6-azaspiro[2.5]octane-6-carboxylate-d₄

To a solution of tert-butyl1-(aminomethyl)-6-azaspiro[2.5]octane-6-carboxylate (1.0 g, 4.16 mmol,1.00 equiv) in DCM (20 mL) at 0° C. was added 4-nitrophenylcarbonochloridate (830 mg, 4.12 mmol, 1.00 equiv) and triethylamine (0.6mL, 4.6 mmol, 1.10 equiv). The resulting solution was stirred at rt for2 h. A solution of triethylamine (1.5 mL) in DCM (80 ml) followed by2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-d4 hydrochloride (700 mg, crude)were added. The reaction mixture was stirred at 25° C. for 3 h thenwashed with 1×100 mL of sodium bicarbonate, 1×100 mL of water and 1×100mL of brine. The organic layer was dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was purified on a silica gelcolumn eluted with DCM/MeOH (95/5) to give 500 mg of tert-butyl1-[({1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl}carbonylamino)methyl]-6-azaspiro[2.5]octane-6-carboxylate-d4as a yellow solid. LC/MS (Method I, ESI): RT=1.17 min, m z=391.0 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆, ppm): δ 8.47 (s, 1H), 8.46 (d, J=4.5 Hz, 1H),7.38 (d, J=4.2 Hz, 1H), 6.34 (s, 1H), 3.51-3.41 (m, 2H), 3.22-3.02 (m,4H), 1.62-1.55 (m, 1H), 1.42-1.35 (m, 11H), 1.22-1.08 (m, 1H), 0.99-0.92(m, 1H), 0.51-0.39 (m, 1H), 0.22-0.17 (m, 1H).

Step 2.N-{6-Azaspiro[2.5]octan-1-ylmethyl}-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamide-d₄

To a solution of tert-butyl1-[({1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl}carbonylamino)methyl]-6-azaspiro[2.5]octane-6-carboxylate-d₄(500 mg, 1.00 equiv) in DCM (15 mL) was added CF₃COOD (2 mL) dropwise atrt. The resulting solution was stirred at rt for 1 h then concentratedunder vacuum. The residue was dissolved in 10 mL of MeOH. The pH of thesolution was adjusted to 8 with saturated aqueous sodium carbonatesolution. The resulting mixture was concentrated under vacuum to give1.5 g of crudeN-{6-azaspiro[2.5]octan-1-ylmethyl}-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamide-d₄as a yellow solid LC/MS (Method I, ESI): RT=0.82 min, m z=291.0 [M+H]⁺.

Step 3

A solution ofN-{6-azaspiro[2.5]octan-1-ylmethyl}-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamide-d₄(500 mg, crude), 3-methyloxetan-3-yl 4-nitrophenyl carbonate (136 mg,0.54 mmol, 1.2 equiv) and triethylamine (91 mg, 0.90 mmol, 2.0 equiv) inDCM (15 mL) was stirred at rt for 5 h. The reaction mixture was dilutedwith 50 mL of DCM and then washed with 1×50 mL of sodium bicarbonate,1×50 mL of water and 1×50 mL of brine. The organic layer was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasfirst purified on a silica gel column eluted with DCM/MeOH (95/5). Thepartially purified product (80 mg) was repurified by Prep-HPLC(1#-Pre-HPLC-005(Waters): Column, SunFire Prep C18 OBD Column, 5 um,19*150 mm; mobile phase, water with 10 mmol NH₄HCO₃ and CH₃CN (15.0%CH₃CN up to 34.0% in 10 min, up to 95.0% in 2 min, down to 15.0% in 2min); Detector, UV 254/220 nm) to give 47 mg of 3-methyloxetan-3-yl1-[({1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl}carbonylamino)methyl]-6-azaspiro[2.5]octane-6-carboxylate-d₄as a white solid. LC/MS (Method I, ESI): RT=1.39 min, m z=405.0 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆, ppm): δ 8.57 (s, 1H), 8.46 (d, J=5.1 Hz, 1H),7.38 (d, J=5.1 Hz, 1H), 6.42 (t, J=5.1 Hz, 1H), 4.64-4.58 (m, 2H),4.42-4.36 (m, 2H), 3.50-3.47 (m, 2H), 3.31-3.28 (m, 2H), 3.16-3.06 (m,2H), 1.62 (s, 3H), 1.64-1.56 (m, 1H), 1.40-1.36 (m, 2H), 1.20-1.17 (m,1H), 1.00-0.96 (m, 1H), 0.49-0.47 (m, 1H), 0.24-0.20 (m, 1H).

Example 419(3-Methyloxetan-3-yl)(2S)-2-[(1,3-dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-6-azaspiro[2.5]octane-6-carboxylate

Step 1. tert-Butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate

A mixture of tert-butyl 4-oxopiperidine-1-carboxylate (300 g, 1.51 mol,1.00 equiv), ethyl 2-(diethoxyphosphoryl)acetate (405 g, 1.81 mol, 1.20equiv) and potassium carbonate (314 g, 2.26 mol, 1.50 equiv) in DMF (4.5L) was stirred overnight at 80° C. The reaction was cooled to rt andthen quenched by the addition of 5 L of water/ice. The precipitate wascollected by filtration and air-dried to give 252 g (62%) of tert-butyl4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate as a white solid.TLC: ethyl acetate/petroleum ether=1:2, R_(f)=0.6.

Step 2. 6-tert-Butyl 1-ethyl 6-azaspiro[2.5]octane-1,6-dicarboxylate

A solution of trimethylsulfoxonium iodide (618 g, 2.81 mol, 3.00 equiv)and t-BuOK (315 g, 2.81 mol, 3.00 equiv) in DMSO (5 L) was stirred at rtfor 1 h. tert-Butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate(252 g, 935.63 mmol, 1.00 equiv) was then added in several portions. Thereaction mixture was stirred at rt overnight and then quenched by theaddition of 10 L of saturated NH₄Cl solution. The resulting mixture wasextracted with 3×3 L of ethyl acetate. The organic combined layers werewashed with 2×1.5 L of brine. The organic layer was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedon a silica gel column eluted with ethyl acetate/petroleum ether (1/10)to give 147 g of 6-tert-butyl 1-ethyl6-azaspiro[2.5]octane-1,6-dicarboxylate as yellow oil. TLC: ethylacetate/petroleum ether=1:2, R_(f)=0.5.

Step 3. 6-[(tert-Butoxy)carbonyl]-6-azaspiro[2.5]octane-1-carboxylicacid

To a stirred solution of 6-tert-butyl 1-ethyl6-azaspiro[2.5]octane-1,6-dicarboxylate (147 g, 1.00 equiv) in ethanol(1 L) at 0° C. was added dropwise a solution of sodium hydroxide (104 g,2.60 mol, 5.00 equiv) in water (200 mL). The resulting solution wasstirred at rt overnight. The reaction mixture was concentrated to removethe excess ethanol. Water (2 L) was added and the mixture was washedwith 3×500 mL of ethyl acetate. The aqueous layer was collected and thepH of the solution was adjusted to 5-6 with 1M HCl. The resultingmixture was extracted with 4×600 mL of ethyl acetate. The combinedorganic layers were dried over anhydrous sodium sulfate and concentratedunder vacuum to give 129 g of crude6-[(tert-butoxy)carbonyl]-6-azaspiro[2.5]octane-1-carboxylic acid as awhite solid. TLC DCM/MeOH=5:1, R_(f)=0.1.

Step 4. tert-Butyl(1S)-1-[[(1S)-1-phenylethyl]carbamoyl]-6-azaspiro[2.5]octane-6-carboxylate

To a stirred solution of6-[(tert-butoxy)carbonyl]-6-azaspiro[2.5]octane-1-carboxylic acid (129g, 505.27 mmol, 1.00 equiv), DIPEA (196 g, 1.52 mol, 6.02 equiv) and(S)-(−)-1-phenylethanamine (87 g, 717.94 mmol, 1.10 equiv) in DMF (2 L)0° C. was added ()-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (231 g, 607.89 mmol, 1.20 equiv) in severalportions. The resulting solution was stirred at rt overnight and thenwas quenched by the addition of 4.5 L of water/ice. The resultingmixture was extracted with 3×2 L of ethyl acetate. The combined organiclayers were washed with 2×800 mL of brine, dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified on asilica gel column eluted with ethyl acetate/petroleum ether (1/4) togive 83.15 g (46%) of tert-butyl1-[[(1S)-1-phenylethyl]carbamoyl]-6-azaspiro[2.5]octane-6-carboxylate asa mixture of diastereomers as a white solid. LC/MS (Method I, ESI):RT₁—4.63 min, RT₂—4.73 min, m z—359.1 [M+H]⁺. The resulting mixture ofdiastereomers was separated by chiral supercritical fluid chromatography(Column: 3×25 cm, 5 um Chiralpak AD; Mobile phase A: CO2; Mobile phaseB: 0.1% NH4OH in MeOH; Isocratic conditions: 87:13 A:B; Flow rate: 200g/min; UV: 220 nm; Back pressure: 100 bar; Column temperature: 40° C.).The first eluting diastereomer was carried forward into the next step.

Step 5. (1S)—N-[(1S)-1-Phenylethyl]-6-azaspiro[2.5]octane-1-carboxamide

Hydrogen chloride gas was bubbled into a solution of tert-butyl(1S)-1-[[(1S)-1-phenylethyl]carbamoyl]-6-azaspiro[2.5]octane-6-carboxylate(20 g, 55.79 mmol, 1.00 equiv) in MeOH (200 mL) at 0° C. for 30 min. Theresulting solution was stirred overnight at rt and then concentratedunder vacuum. The residue was diluted with 100 mL of H₂O and the pH ofthe solution was adjusted to 12 with 2N sodium hydroxide solution. Theresulting mixture was extracted with 3×100 mL of DCM. The combinedorganic layers was dried over anhydrous sodium sulfate and concentratedunder vacuum to give 15 g of(1S)—N-[(1S)-1-phenylethyl]-6-azaspiro[2.5]octane-1-carboxamide as alight yellow solid. LC/MS (Method I, ESI): RT=1.03 min, m z=259.0[M−H]⁻.

Step 6. tert-Butyl(1S)-1-([[(1S)-1-phenylethyl]amino]methyl)-6-azaspiro[2.5]octane-6-carboxylate

To a stirred solution of(1S)—N-[(1S)-1-phenylethyl]-6-azaspiro[2.5]octane-1-carboxamide (8 g,30.96 mmol, 1.00 equiv) in THF (800 mL) maintained under nitrogen at rtwas added a 1 M solution of borane in THF (100 mL, 100 mmol, 3.3 equiv)dropwise. The resulting solution was refluxed overnight. The resultingmixture was concentrated under vacuum then water (50 mL) was added tothe residue. The pH of the solution was adjusted to 1 with 5% HCl (5%).The resulting solution was stirred at reflux for 4 h. The reactionmixture was cooled to rt and the pH of the solution was adjusted to 12with a 10% sodium hydroxide solution. The solution was cooled to 0° C.then a solution of di-tert-butyl dicarbonate (6.7 g, 30.70 mmol, 0.68equiv) in 20 mL of THF was added dropwise with stirring. The reactionmixture was stirred overnight at rt. The resulting mixture was extractedwith 2×200 mL of ethyl acetate. The combined organic layers were driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas purified on a silica gel column eluted with ethyl acetate/petroleumether (1:3) to give 2.9 g (19%) of tert-butyl(1S)-1-([[(1S)-1-phenylethyl]amino]methyl)-6-azaspiro[2.5]octane-6-carboxylateas light brown oil. TLC: DCM:MeOH-10:1. R_(f)=0.3.

Step 7. tert-Butyl(1S)-1-(aminomethyl)-6-azaspiro[2.5]octane-6-carboxylate

A mixture of tert-butyl(1S)-1-([[(1S)-1-phenylethyl]amino]methyl)-6-azaspiro[2.5]octane-6-carboxylate(700 mg, 2.03 mmol, 1.00 equiv) and Pd(OH)₂ (100 mg) in MeOH (30 mL) wasstirred under 5 atmosphere of H₂ in a 50-mL pressure reactor overnightat it. The catalyst was removed by filtration. The filtrate wasconcentrated under vacuum to afford 400 mg (82%) of tert-butyl(1S)-1-(aminomethyl)-6-azaspiro[2.5]octane-6-carboxylate as a lightyellow oil. LC/MS (Method F, ESI): RT=1.25 min, m/z=241.0 [M+H]⁺.

Step 8. tert-Butyl(1S)-1-[[([1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]carbonyl)amino]methyl]-6-azaspiro[2.5]octane-6-carboxylate

A solution of tert-butyl(1S)-1-(aminomethyl)-6-azaspiro[2.5]octane-6-carboxylate (5 g, 20.80mmol, 1.00 equiv), 4-nitrophenyl chloroformate (4.4 g, 21.83 mmol, 1.05equiv) and DIPEA (10 mL) in THF (200 mL) was stirred overnight at rt.1H,2H,3H-Pyrrolo[3,4-c]pyridine dihydrochloride (4.4 g, 22.79 mmol, 9.24equiv) was then added and the reaction mixture was stirred overnight atrt. The resulting mixture was concentrated under vacuum. The residue waspurified on a silica gel column eluted with DCM/MeOH (20/1) to give 2.3g of tert-butyl(1S)-1-[[([1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]carbonyl)amino]methyl]-6-azaspiro[2.5]octane-6-carboxylateas a light yellow solid TLC: DCM:MeOH=10:1, R_(f)=0.4.

Step 9.N-[(1S)-6-Azaspiro[2.5]octan-1-ylmethyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamidehydrochloride

A solution of tert-butyl(1S)-1-[[([1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]carbonyl)amino]methyl]-6-azaspiro[2.5]octane-6-carboxylate (2.3 g, 5.95 mmol,1.00 equiv) in a saturated hydrogen chloride in MeOH solution (100 mL)was stirred at rt for 2 h. The resulting mixture was concentrated undervacuum to yield 1.7 g of crudeN-[(1S)-6-azaspiro[2.5]octan-1-ylmethyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamidehydrochloride as a brown solid.

Step 10. 3-Methyloxetan-3-yl 4-nitrophenyl carbonate

To a stirred solution of oxetan-3-one (9 g, 124.89 mmol, 1.00 equiv) inTHF (200 mL) maintained under nitrogen at −50° C. was added dropwise a1.6M solution of methyllithium in ether (150 mL, 240 mmol, 1.9 equiv).The reaction mixture was warmed to 0° C. and stirred for 2 h. A solutionof 4-nitrophenyl chloroformate (26 g, 128.99 mmol, 1.03 equiv) in THF(100 mL) was then added dropwise at 0° C. The resulting solution wasstirred for another 2 h at rt after the addition was completed. Thereaction was then quenched by the addition of 200 mL of water. Theresulting mixture was extracted with 2×200 mL of ethyl acetate. Thecombined organic layers was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified on a silica gelcolumn eluted with ethyl acetate/petroleum ether (1:5) to give 4.5 g(14%) of 3-methyloxetan-3-yl 4-nitrophenyl carbonate as a white solid.TLC petroleum ether:ethyl acetate=2:1, R_(f)=0.6.

Step 11

A solution ofN-[(1S)-6-azaspiro[2.5]octan-1-ylmethyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carboxamidehydrochloride (1.7 g, 5.27 mmol, 1.00 equiv), 3-methyloxetan-3-yl4-nitrophenyl carbonate (1.7 g, 6.71 mmol, 1.27 equiv) and DIPEA (2 mL)in ethanol (50 mL) was stirred overnight at rt. The resulting mixturewas concentrated under vacuum. The residue was dissolved in 150 mL ofDCM and then washed with 100 mL of H₂O. The organic layer was dried overanhydrous sodium sulfate then concentrated under vacuum. The residue waspurified on a silica gel column eluted with DCM/MeOH (20/1) to give 1.43g (68%) of 3-methyloxetan-3-yl(1S)-1-[[([1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]carbonyl)amino]methyl]-6-azaspiro[2.5]octane-6-carboxylateas a white solid. LC/MS (Method I, ESI): RT=1.24 min, m z=401.1 [M+H]⁺.¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 8.56 (s, 1H), 8.47 (d, J 5.1 Hz, 1H),7.39 (d, J 5.1 Hz, 2H), 6.42 (t, J 5.2 Hz, 1H), 4.63-4.59 (m, 6H), 4.38(d, J 7.5 Hz, 2H), 3.48 (s, 2H), 3.31 (s, 2H), 3.12 (t, J 6.0 Hz, 2H),1.62 (s, 3H), 1.59-1.55 (m, 1H), 1.42-1.39 (m, 2H), 1.37-1.34 (m, 1H),1.21-1.17 (m, 1H), 1.01-0.96 (m, 1H), 0.54-0.48 (m, 1H), 0.27-0.21 (m,1H).

Additional example compounds were prepared using methods analogous tothose described above. Particular example compounds were prepared usingmethods analogous to those indicated for the Example numbers listedbelow:

Ex. Method of Example No. 22 6 23 6 24 6 25 1 26 339 27 339 28 339 29339 30 339 31 339 32 339 33 339 34 339 35 339 36 339 37 339 38 339 39339 40 6 41 383 42 383 43 339 44 339 45 1 and 6 46 6 47 1 and 6 48 1 491 50 339 51 339 52 339 53 339 54 339 55 339 56 339 57 339 58 339 59 33960 339 61 339 62 339 63 339 64 339 65 339 66 339 67 339 68 339 69 339 70339 71 339 72 339 73 339 74 339 75 339 76 339 77 339 78 339 79 339 80339 81 339 82 339 83 339 84 339 85 339 86 339 87 339 88 339 89 339 90339 91 339 92 339 93 339 94 339 95 339 96 339 97 339 98 339 99 339 100339 101 339 102 339 103 339 104 339 105 339 106 339 107 339 108 339 109339 110 339 111 339 112 339 113 339 114 339 115 339 116 339 117 339 118339 119 339 120 339 121 339 122 339 123 339 124 339 125 339 126 339 127339 128 339 129 339 130 339 131 339 132 339 133 339 134 339 135 339 136339 137 339 138 339 139 339 140 339 141 339 142 339 143 339 144 339 145339 146 339 147 339 148 6 149 6 151 1 152 339 153 339 154 339 155 339156 339 157 159 158 159 160 159 161 159 162 159 163 159 164 159 165 159166 159 167 159 168 159 169 159 170 159 171 159 172 159 173 159 175 150176 1 and 6 177 1 and 6 178 1 and 6 179 339 180 339 181 339 182 159 183159 184 159 185 159 186 159 187 159 188 1 and 6 189 1 and 6 190 1 and 6191 6 192 6 193 1 194 1 195 150 196 6 197 6 198 6 199 6 200 1 201 1 and6 202 1 and 6 203 6 204 419 205 419 206 6 207 1 and 6 208 6 209 6 210 6211 6 212 1 213 6 214 6 215 419 216 6 218 1 219 150 220 150 221 150 222339 223 339 228 1 229 6 230 1 and 6 231 339 232 339 233 339 234 339 235339 236 339 237 339 238 339 239 339 240 339 241 339 242 339 243 339 244339 245 339 246 339 247 339 248 339 249 339 250 339 251 339 252 339 253339 254 339 255 339 256 339 257 339 258 339 259 339 260 339 261 339 262339 263 339 264 339 265 339 266 339 267 339 268 339 269 339 270 339 271339 272 339 273 339 275 6 276 174 277 6 278 6 279 1 and 6 280 339 281339 282 339 283 339 284 339 285 6 286 6 287 6 288 6 289 6 290 6 291 6292 1 and 6 293 6 294 339 295 339 296 339 297 339 298 339 299 339 300339 301 339 302 339 303 339 304 339 305 339 306 339 307 339 308 339 309339 310 339 311 339 312 339 313 339 314 339 315 339 316 339 317 339 318339 319 339 320 339 321 339 322 339 323 339 324 339 325 339 326 339 327339 328 339 329 339 330 339 331 339 332 339 333 339 334 339 335 339 336339 337 339 338 339 340 339 341 339 343 6 344 6 345 6 346 1 and 6 347 1and 6 348 6 350 1 351 1 352 1 and 6 353 1 and 6 354 1 and 6 355 1 and 6356 6 357 1 and 6 358 6 359 6 360 1 and 6 361 1 362 339 363 339 364 6365 1 and 6 366 1 and 6 367 409 368 6 369 6 370 6 371 6 372 6 373 6 3751 376 1 and 6 377 6 378 6 379 6 381 6 382 1 384 339 385 339 387 6 388 1389 6 392 1 393 1 and 6 395 1 396 1 and 6 397 6 398 1 and 6 399 6 400174 401 6 402 6 404 1 and 6 407 1 and 6 408 409 410 409 411 6 413 419414 419 415 1 and 6 416 1 and 6 417 1 and 6 418 1 and 6

Additional examples were prepared using methods analogous to thosedescribed above.

Analytical Characterization:

Each of the specifically exemplified compounds described herein wasprepared using the methods analogous to those described above, and wereanalyzed by LC/MS. Data for each compound, along with the LC/MS methodused to generate the data, is provided in Table 1 (NA=not available).

TABLE 1 LC/MS Data for Example Compounds. Retention time Ex. (min) mzMethod 2 1.63 402.0 E 3 3.43 386.1 B 4 1.60 386.0 E 5 3.60 385.1 B 73.44 403.0 C 8 3.19 385.2 L 9 1.40 395.0 H 10 1.16 397.0 H 11 1.43 398.2C 12 1.24 355.0 H 13 2.45 425.2 C 14 1.21 377.0 C 15 4.25 386.0 L 162.39 327.3 J 17 1.27 363.0 A 18 2.23 285.1 M 19 2.41 286.1 M 20 1.71341.2 C 21 2.62 399.0 A 22 3.59 385.1 B 23 2.63 386.1 I 24 1.37 383.2 C25 1.07 387.3 O 26 2.59 394.2 T 27 3.60 410.2 T 28 3.80 482.2 T 29 4.19384.3 T 30 2.83 426.3 T 31 4.06 429.2 T 32 3.79 368.2 T 33 2.99 397.2 T34 3.66 409.2 T 35 3.18 411.3 T 36 3.66 412.3 T 37 3.61 398.2 T 38 3.93400.2 T 39 3.02 405.2 T 40 1.04 482.3 Q 41 4.46 385.2 T 42 4.45 385.3 T43 4.50 386.2 T 44 4.49 386.2 T 45 1.35 385 I 46 1.95 369 B 47 1.31 405I 48 4.36 387.3 T 49 4.35 387.3 T 50 3.48 406.2 T 51 3.57 413.3 T 523.94 412.3 T 53 3.15 411.3 T 54 3.85 413.2 T 55 3.48 413.2 T 56 3.39411.2 T 57 3.45 411.2 T 58 3.91 390.2 T 59 3.54 384.2 T 60 3.63 398.2 T61 3.58 384.2 T 62 3.18 371.2 T 63 3.64 436.3 T 64 3.34 426.3 T 65 3.04427.3 T 66 3.41 432.2 T 67 3.53 422.3 T 68 3.44 425.3 T 69 3.87 468.2 T70 3.60 457.2 T 71 3.79 475.2 T 72 3.70 447.2 T 73 3.79 475.2 T 74 3.65475.2 T 75 2.95 427.3 T 76 3.54 461.2 T 77 3.88 459.2 T 78 3.36 440.3 T79 3.36 440.3 T 80 3.46 446.2 T 81 3.81 472.2 T 82 3.52 439.3 T 83 3.81472.2 T 84 3.79 483.2 T 85 3.87 523.2 T 86 3.29 502.3 T 87 3.41 502.3 T88 3.54 502.3 T 89 2.91 440.3 T 90 3.70 439.3 T 91 2.79 426.3 T 92 3.81468.2 T 93 3.85 468.2 T 94 3.52 448.2 T 95 2.91 454.3 T 96 3.84 486.3 T97 3.12 391.2 T 98 3.56 391.2 T 99 3.49 381.2 T 100 3.19 381.2 T 1012.97 380.2 T 102 3.41 392.2 T 103 3.21 391.2 T 104 3.44 380.2 T 105 2.98394.2 T 106 3.43 394.2 T 107 3.43 394.2 T 108 3.62 394.2 T 109 3.59394.2 T 110 3.33 392.2 T 111 3.39 392.2 T 112 3.46 392.2 T 113 3.32392.2 T 114 3.49 394.2 T 115 3.58 408.2 T 116 3.76 408.2 T 117 3.72395.2 T 118 4.09 396.2 T 119 3.12 405.2 T 120 3.10 405.2 T 121 3.15405.2 T 122 3.65 406.2 T 123 3.85 420.2 T 124 3.74 422.2 T 125 3.72409.2 T 126 3.65 408.2 T 127 3.77 416.2 T 128 3.70 409.2 T 129 3.37476.3 T 130 3.73 354.2 T 131 4.30 462.2 T 132 3.75 461.2 T 133 3.51448.2 T 134 3.42 448.2 T 135 3.70 448.2 T 136 3.91 423.2 T 137 3.88422.2 T 138 3.73 422.2 T 139 3.65 395.2 T 140 3.80 436.3 T 141 3.37380.2 T 142 3.82 489.3 T 143 2.95 413.3 T 144 3.73 439.3 T 145 3.37411.2 T 146 3.27 461.3 T 147 3.74 489.3 T 148 1.29 453 I 149 1.74 425 I150 1.88 397.1 K 151 0.97 373.2 S 152 4.10 429.2 T 153 3.44 372.2 T 1544.64 536.2 T 155 3.38 413.3 T 156 2.97 405.1 T 157 4.07 430.2 T 158 4.24433.3 T 159 4.20 419.2 T 160 4.03 419.2 T 161 4.08 437.2 T 162 4.24433.3 T 163 4.09 437.2 T 164 4.13 449.2 T 165 4.05 449.2 T 166 4.09437.2 T 167 4.03 449.2 T 168 4.51 489.2 T 169 4.71 463.3 T 170 4.31453.2 T 171 4.25 453.2 T 172 3.47 357.2 T 173 4.53 489.2 T 174 1.66 412I 175 2.58 399 B 176 1.67 406.1 B 177 2.32 406.2 K 178 2.1 429.9 C 1793.71 457.2 T 180 3.13 408.2 T 181 3.48 422.2 T 182 3.83 385.3 T 183 3.59371.2 T 184 4.35 425.3 T 185 3.63 371.2 T 186 4.12 411.3 T 187 3.98405.2 T 188 1.09 454.1 C 189 1.9 371.1 B 190 1.61 406.1 B 191 1.52 340.1K 192 1.21 359.2 F 193 1.55 399.2 G 194 1.57 344.1 G 195 1.39 398.1 K196 2.05 411.3 F 197 1.6 425 C 198 0.87 414.2 F 199 1.43 418.9 C 2001.49 401.2 I 201 1.33 441.3 F 202 3.49 473.1 B 203 1.31 384.2 I 204 3.10396.6 T 205 4.13 430.2 T 206 1.33 428 I 207 1.88 430 I 208 1.92 406.2 F209 1.04 441.9 C 210 1.29 420 I 211 1.98 440.9 C 212 2.04 386.3 F 2134.11 383.3 T 214 4.12 383.3 T 215 3.83 402.2 T 216 1.32 428 I 218 2.12439.2 C 219 1.27 413.2 L 220 1.06 423.3 F 221 1.21 395.2 R 222 3.74450.3 T 223 4.12 502.3 T 228 1.41 399.2 Q 229 3.24 428.2 B 230 2.24 441I 231 3.42 405.2 T 232 3.10 405.2 T 233 2.98 405.2 T 234 3.35 405.2 T235 3.42 405.2 T 236 3.18 430.2 T 237 3.75 430.2 T 238 3.43 431.2 T 2393.32 430.2 T 240 3.59 430.2 T 241 2.93 430.2 T 242 3.78 415.2 T 243 3.76415.2 T 244 3.90 502.2 T 245 3.12 489.3 T 246 3.24 484.3 T 247 4.36474.2 T 248 3.26 473.3 T 249 3.56 471.2 T 250 3.59 471.2 T 251 3.52471.3 T 252 3.21 470.3 T 253 3.09 456.2 T 254 3.47 458.2 T 255 3.14458.2 T 256 3.96 459.2 T 257 3.96 459.2 T 258 3.64 461.2 T 259 3.41469.2 T 260 3.36 470.2 T 261 3.61 442.2 T 262 3.21 442.2 T 263 3.07444.2 T 264 3.55 447.2 T 265 3.00 448.1 T 266 3.94 432.2 T 267 3.28442.2 T 268 3.00 442.2 T 269 3.88 442.2 T 270 3.50 442.2 T 271 3.36442.2 T 272 3.44 381.2 T 273 3.85 370.2 T 274 1.49 376.2 Q 275 1.7 439 A276 1.28 413.2 R 277 1.34 404.2 J 278 2.56 404.1 B 279 1.62 409.2 B 2803.89 472.2 T 281 3.09 419.2 T 282 3.36 384.2 T 283 3.43 400.2 T 284 3.39386.2 T 285 1.71 404.1 B 286 0.92 407.1 R 287 1.42 407.2 R 288 1.02426.1 R 289 1.78 421.2 R 290 1.15 427.3 C 291 0.9 404.2 R 292 1.6 409.1B 293 0.98 421.2 R 294 3.91 464.3 T 295 4.04 498.3 T 296 4.15 450.3 T297 3.58 408.2 T 298 3.94 450.3 T 299 3.59 408.2 T 300 3.43 422.2 T 3013.43 422.2 T 302 3.77 430.2 T 303 3.22 491.3 T 304 3.35 491.3 T 305 3.82475.2 T 306 4.03 521.3 T 307 3.04 463.2 T 308 3.88 450.3 T 309 3.14444.2 T 310 3.83 444.2 T 311 3.19 444.2 T 312 3.88 448.2 T 313 3.34431.2 T 314 3.47 436.3 T 315 3.39 444.2 T 316 3.62 430.2 T 317 3.00430.2 T 318 4.53 423.2 T 319 4.13 436.3 T 320 3.19 431.2 T 321 3.42431.2 T 322 3.92 436.3 T 323 3.76 422.2 T 324 3.49 422.2 T 325 3.67422.2 T 326 3.73 422.2 T 327 3.94 421.2 T 328 4.41 421.1 T 329 3.15408.2 T 330 3.29 408.2 T 331 3.39 395.2 T 332 3.41 420.2 T 333 3.65420.2 T 334 3.57 409.2 T 335 3.35 408.2 T 336 3.23 381.2 T 337 3.39381.2 T 338 2.63 380.2 T 339 1.12 488.3 F 340 3.12 431.2 T 341 3.49305.2 T 343 0.99 501.3 C 344 1.4 501.3 C 345 1.02 446.3 C 346 1.42 503.4F 347 2.51 409.2 B 348 1.37 381 I 350 2.11 401.2 F 351 1.16 403.3 F 3520.94 406.3 F 353 1.87 421.3 F 354 1.11 462.3 F 355 1.14 410.2 F 356 1.37440.4 C 357 1.99 430.3 F 358 1.24 466 C 359 0.76 412.2 O 360 2.85 401.2B 361 2.38 400.2 O 362 2.02 489.4 F 363 1.03 487.3 F 364 2.24 381.2 F365 1.06 423.3 F 366 1.06 423.3 F 367 2 391.2 K 368 1.29 419 I 369 1.35460.2 O 370 0.74 408.3 S 371 1.76 423.2 I 372 1.2 517.4 F 373 1.75 382.2O 375 1.23 415.3 F 376 1.78 403.3 F 377 2.03 383.3 O 378 1.78 420.1 K379 1.64 419 I 381 2.43 421.2 K 382 0.9 411.2 O 383 1.48 386.0 S 3844.65 409.2 U 385 4.76 409.2 U 387 1.3 415.2 K 388 2.68 502.4 C 389 1.24405.3 C 392 1.42 414.2 F 393 1.68 417.3 F 394 1.01 421.1 C 395 1.09400.2 F 396 1.3 449.3 F 397 1.85 399.3 F 398 1.44 460.2 O 399 1.19 428 F400 1.76 411 I 401 1.41 401 I 402 1.71 386.3 P 403 1.15 508 I 404 1.16426 I 405 1.25 488 I 406 1.65 402.2 K 407 1.6 407 I 408 1.27 375 I 4091.39 405 I 410 1.15 414 I 411 2.19 390 I 413 1.26 371.2 I 414 1.3 371.2I 415 1.25 396.2 F 416 1.58 372.2 F 417 1.33 400.1 I 418 1.43 391.1 I419 1.24 401.1 I

It is understood that the person skilled in the art will be able toprepare the compounds of the present invention using methods known inthe art along with the general method of synthesis described herein.

Assay 1: Biochemical Inhibition Assay

NAMPT Protein Purification.

Recombinant His-tagged NAMPT was produced in E. coli cells, purifiedover a Ni column, and further purified over a size-exclusion column byXTAL Biostructures.

The NAMPT Enzymatic Reaction.

The NAMPT enzymatic reactions were carried out in Buffer A (50 mM HepespH 7.5, 50 mM NaCl, 5 mM MgCl₂, and 1 mM THP) in 96-well V-bottomplates. The compound titrations were performed in a separate dilutionplate by serially diluting the compounds in DMSO to make a 100× stock.Buffer A (89 μL) containing 33 nM of NAMPT protein was added to 1 μL of100× compound plate containing controls (e.g. DMSO or blank). Thecompound and enzyme mixture was incubated for 15 min at roomtemperature, then 10 μL of 10× substrate and co-factors in Buffer A wereadded to the test well to make a final concentration of 1 μM NAM, 100 μM5-Phospho-D-ribose 1-diphosphate (PRPP), and 2.5 mM Adenosine5′-triphosphate (ATP). The reaction was allowed to proceed for 30 min atroom temperature, then was quenched with the addition of 11 μL of asolution of formic acid and L-Cystathionine to make a finalconcentration of 1% formic acid and 10 μM L-Cystathionine Background andsignal strength was determined by addition (or non-addition) of a serialdilution of NMN to a pre-quenched enzyme and cofactor mix.

Quantification of NMN.

A mass spectrometry-based assay was used to measure the NAMPT reactionproduct, β-nicotinamide mononucleotide (NMN), and the internal control(L-Cystathionine) NMN and L-Cystathionine were detected using theservices of Biocius Lifesciences with the RapidFire system. In short,the NMN and L-Cystathionine were bound to a graphitic carbon cartridgein 0.1% formic acid, eluted in 30% acetonitrile buffer, and injectedinto a Sciex 4000 mass spectrometer. The components of the sample wereionized with electrospray ionization and the positive ions weredetected. The Q1 (parent ion) and Q3 (fragment ion) masses of NMN were334.2 and 123.2, respectively. The Q1 and Q3 for L-Cystathionine were223.1 and 134.1, respectively. The fragments are quantified and theanalyzed by the following method.

Determination of IC₅₀ Values.

First, the NMN signal was normalized to the L-Cystathionine signal bydividing the NMN signal by the L-Cystathionine signal for each well. Thesignal from the background wells were averaged and subtracted from thetest plates. The compound treated cells were then assayed for percentinhibition by using this formula:

% Inh=100−100*x/y

wherein x denotes the average signal of the compound treated wells and ydenotes the average signal of the DMSO treated wells.

IC₅₀ values were then determined using the following formula:

IC ₅₀=10̂(LOG₁₀(X)+(((50-% Inh at Cmpd Concentration1)/(XX−YY)*(LOG₁₀(X)−LOG₁₀(Y))))

wherein X denotes the compound concentration 1, Y denotes the compoundconcentration 2, XX denotes the % inhibition at compound concentration 1(X), and YY denotes the % inhibition at compound concentration 2 (Y).

The compounds of this invention have IC₅₀ values that are preferablyunder 1 μM, more preferably under 0.1 μM, and most preferably under 0.01μM. Results for the compounds tested in this assay are provided in Table2 below.

Assay 2: In-Vitro Cell Proliferation Assay

Assay Method.

A2780 cells were seeded in 96-well plates at 1×10³ cells/well in 180 μLof culture medium (10% FBS, 1% Pen/Strep Amphotecricin B, RPMI-1640)with and without the addition of either NMN or nicotinamide (NAM). Afterovernight incubation at 37° C. and 5% CO₂, the compound titrations wereperformed in a separate dilution plate by serially diluting thecompounds in DMSO to make a 1000× stock. The compounds were then furtherdiluted to 10× final concentration in culture media, whereupon 20 μL ofeach dilution was added to the plated cells with controls (e.g. DMSO andblank) to make a final volume of 200 μL The final DMSO concentration ineach well was 0.1%. The plates were then incubated for 72 hours at 37°C. in a 5% CO₂ incubator. The number of viable cells was then assessedusing sulforhodamine B (SRB) assay. Cells were fixed at 4° C. for 1 hourwith the addition of 50 μL 30% trichloroacetic acid (TCA) to make afinal concentration of 6% TCA. The plates were washed four times withH₂O and allowed to dry for at least 1 hour, whereupon 100 μL of a 4% SRBin 1% acetic acid solution was added to each well and incubated at roomtemperature for at least 30 min. The plates were then washed three timeswith 1% acetic acid, dried, and treated with 100 μL of 10 mM Tris-Basesolution. The plates were then read in a microplate reader at anabsorbance of 570 nm. Background was generated on a separate plate withmedia only.

Determination of IC₅₀ Values.

First, the signals from the background plate were averaged, then thebackground was subtracted from the test plates. The compound-treatedcells were then assayed for % inhibition by using the following formula:

% Inh=100−100*x/y

wherein x denotes the average signal of the compound-treated cells and ydenotes the average signal of the DMSO-treated cells.

IC₅₀ values were then determined using the following formula:

IC ₅₀=10̂(LOG₁₀(X)+(((50-% Inh at Cmpd Concentration1)/(XX−YY)*(LOG₁₀(X)−LOG₁₀(Y))))

wherein X denotes the compound concentration 1, Y denotes the compoundconcentration 2, XX denotes the % inhibition at compound concentration 1(X), and YY denotes the % inhibition at compound concentration 2 (Y).

Specificity of Cytotoxicity.

Inhibition of NAMPT could be reversed by the addition of NAM or NMN. Thespecificity of the compounds were determined via cell viability assay inthe presence of the compound and either NAM or NMN. Percent inhibitionswere determined using the method given above.

The compounds of this invention have IC₅₀ values that are preferablyunder 1 μM, more preferably under 0.1 μM, and most preferably under 0.01μM. Most preferable compounds of this invention are compounds that haveIC₅₀ values in the enzymatic assay and the cell proliferation assay thatare both under 1 μM, more preferably both of the values are under 0.1μM, and most preferably both of the values are under 0.01 μM. Resultsfor the compounds tested in this assay are provided in Table 2 (NT=nottested).

TABLE 2 Biochemical and Cell Proliferation Assay Results. BiochemicalCell Proliferation Ex. (IC₅₀) [uM] (IC₅₀) [uM] 1 0.00432 0.000775 20.00719 0.202 3 0.00896 0.0697 4 0.00953 0.0489 5 0.0183 0.119 6 0.04540.00533 7 0.0648 0.0962 8 0.0735 0.208 9 0.108 0.221 10 0.208 0.791 110.255 2.000 12 0.398 2.000 13 0.423 2.000 14 0.988 2.000 15 2.000 NT 162.000 2.000 17 2.000 2.000 18 NT NT 19 NT NT 20 0.39832 2.000 21 0.1752.000 22 0.0175 0.119 23 0.0100 0.0325 24 0.0511 0.00829 25 0.00680.0013 26 0.304 2.0 27 0.0504 0.842 28 0.0642 0.616 29 0.0111 0.00303 300.416 0.614 31 0.0373 0.0121 32 0.153 2.0 33 1.12 2.0 34 0.0542 0.379 350.563 2.0 36 0.0893 0.185 37 0.155 0.643 38 0.040 0.0188 39 0.047 0.23240 0.13 0.0243 41 0.0143 0.0861 42 0.143 2.0 43 0.279 2.0 44 0.01990.0289 45 0.00623 0.00158 46 0.12 0.402 47 0.00459 0.0126 48 0.009960.000995 49 0.0479 0.0335 50 0.309 2.0 51 0.173 0.367 52 0.135 0.674 530.42 0.846 54 2.0 2.0 55 1.06 2.0 56 0.575 2.0 57 0.223 1.6 58 0.422 2.059 0.782 2.0 60 0.309 1.53 61 0.768 2.0 62 0.395 2.0 63 0.177 1.39 640.398 2.0 65 0.526 0.931 66 1.04 2.0 67 0.21 0.193 68 0.812 0.414 690.386 0.194 70 0.0681 0.492 71 0.0641 0.0137 72 0.0338 0.0481 73 0.05740.0258 74 0.231 0.169 75 0.109 0.0809 76 0.214 0.228 77 0.169 1.15 780.296 2.0 79 0.755 2.0 80 0.244 1.34 81 0.626 2.0 82 0.398 0.71 83 0.2111.08 84 0.0767 0.185 85 0.0388 0.0142 86 0.030 0.00453 87 0.802 2.0 880.022 0.00977 89 0.228 0.116 90 0.149 0.183 91 0.474 2.0 92 0.180 0.15293 0.475 0.878 94 0.0706 0.437 95 0.426 2.0 96 0.153 0.711 97 0.421 2.098 0.504 2.0 99 0.826 2.0 100 0.462 2.0 101 0.625 2.0 102 1.21 2.0 1030.44 2.0 104 2.92 2.0 105 0.246 0.755 106 0.396 0.743 107 0.372 2.0 1080.216 0.449 109 0.0993 0.299 10 0.861 2.0 11 0.579 2.0 12 0.417 2.0 130.877 2.0 14 0.325 2.0 15 0.0499 0.0376 116 0.365 0.37 117 0.422 0.752118 0.449 1.07 119 0.188 0.446 120 0.207 0.0928 121 0.308 1.09 1220.0974 2.0 123 0.0661 0.083 124 0.151 0.124 125 0.0955 0.221 126 0.2730.833 127 0.269 2.0 128 0.0914 0.0292 129 0.10 0.0373 130 2.0 2.0 1310.356 0.326 132 0.0432 0.0072 133 0.194 0.696 134 0.0477 0.514 1350.0509 0.0364 136 0.104 0.169 137 0.252 0.116 138 0.0941 2.0 139 0.1632.0 140 0.78 2.0 141 0.222 2.0 142 0.116 0.0971 143 1.22 2.0 144 0.1160.375 145 0.494 2.0 146 0.0801 0.0745 147 0.0553 0.0744 148 0.288 0.102149 0.768 0.496 150 0.31 0.265 151 0.0148 0.00423 152 0.0601 0.262 1530.686 2.0 154 0.208 2.61 155 0.261 2.0 156 NT NT 157 0.0752 2.0 158 0.412.0 159 0.0332 0.274 160 0.951 2.0 161 0.123 2.0 162 0.441 2.0 163 0.5592.0 164 0.118 1.54 165 0.309 2.0 166 0.406 2.0 167 0.314 2.0 168 0.1132.0 169 0.0558 0.0278 170 0.161 2.0 171 0.0604 2.0 172 0.422 2.0 1730.146 2.0 174 0.238 0.197 175 0.0467 0.0111 176 0.0376 0.0341 177 0.03630.0344 178 0.0257 0.0323 179 0.034 0.0254 180 2.0 2.46 181 0.01730.00331 182 0.255 2.0 183 0.314 2.0 184 0.422 2.0 185 0.502 2.0 1860.0972 0.732 187 0.0446 2.46 188 0.0301 0.0453 189 0.0128 0.00438 1900.0312 0.0507 191 0.156 1.04 192 0.0239 0.0294 193 0.212 2.0 194 0.6682.0 195 0.0785 0.218 196 0.0144 0.00367 197 0.0111 0.00961 198 0.1310.0618 199 0.0144 0.184 200 0.00456 0.0247 201 0.0173 0.0279 202 0.0120.0282 203 0.544 2.0 204 0.00636 0.00336 205 0.108 0.13 206 0.263 2.0207 0.0491 0.136 208 0.0347 0.0261 209 0.0803 0.203 210 0.0588 0.316 2110.0278 0.131 212 0.0528 0.0207 213 0.0318 0.00578 214 0.936 2.0 2150.0751 0.0658 216 0.179 1.34 218 0.00997 0.00159 219 0.0151 0.00531 2200.0034 0.00622 221 0.0178 0.0254 222 0.0504 0.0117 223 0.027 0.00192 2280.0222 0.00474 229 0.0548 0.0184 230 0.0185 0.0299 231 0.201 0.516 2320.0983 0.207 233 0.0458 0.288 234 0.161 0.164 235 0.288 1.56 236 0.03390.0473 237 0.0501 0.166 238 0.0317 0.91 239 0.0329 0.0297 240 0.02630.0187 241 0.0273 0.0702 242 0.134 0.713 243 0.0736 0.434 244 0.02640.0261 245 0.0525 0.0126 246 0.0211 0.0138 247 0.205 2.0 248 0.02210.00439 249 0.254 0.935 250 0.549 2.0 251 0.0776 0.215 252 0.0695 0.344253 0.0417 0.0554 254 0.0191 0.013 255 0.0499 0.179 256 0.147 0.596 2570.313 2.0 258 0.0314 0.0203 259 0.161 1.2 260 0.916 2.0 261 0.02450.0158 262 0.0695 0.0795 263 0.0265 0.0254 264 0.0683 0.245 265 2.23 2.0266 0.127 1.47 267 0.321 2.0 268 0.0691 0.0719 269 0.0277 0.016 2700.0192 0.0192 271 0.0964 0.139 272 0.335 2.0 273 0.0178 0.207 274 0.3842.0 275 0.121 0.0177 276 0.0391 0.0132 277 0.445 0.755 278 0.479 2.0 2790.0934 0.00745 280 0.0152 0.00683 281 0.056 0.0185 282 2.0 2.0 283 0.3620.362 284 0.106 0.105 285 2.0 2.0 286 0.027 0.027 287 0.0245 0.0245 2880.0606 0.0606 289 0.00999 0.00999 290 0.00454 0.00454 291 0.722 0.722292 0.693 0.693 293 0.0593 0.0593 294 0.0486 0.0121 295 0.0145 0.000944296 0.0871 0.0108 297 0.0925 0.278 298 0.213 0.103 299 0.165 0.249 3001.13 0.335 301 0.0425 0.00421 302 0.0648 0.0903 303 0.478 2.0 304 0.03130.0329 305 0.0979 0.0612 306 0.0678 0.0388 307 0.0858 0.0267 308 0.1162.0 309 0.0822 0.0247 310 0.119 0.0308 311 0.0158 0.0121 312 0.3680.00961 313 0.0363 0.0159 314 0.0459 0.00676 315 0.0572 0.104 316 0.7442.0 317 0.0443 0.0152 318 0.436 2.0 319 0.0776 0.055 320 0.13 0.549 3210.523 2.0 322 0.0282 0.0151 323 0.613 2.0 324 0.137 0.109 325 0.06980.0247 326 0.0339 0.0109 327 0.159 0.0776 328 0.040 0.0834 329 0.0500.0551 330 0.0806 0.159 331 0.0243 0.00704 332 0.0169 0.0338 333 0.2970.00681 334 0.0599 0.0565 335 0.32 0.59 336 0.0378 0.0635 337 0.02750.0231 338 0.169 2.0 339 0.0138 0.0019 340 0.0663 0.429 341 0.162 0.717343 0.0541 0.0425 344 0.0973 0.072 345 0.14 0.0808 346 0.0103 0.00601347 0.0113 0.00393 348 0.102 0.0426 350 0.0273 0.00396 351 0.02880.00356 352 0.0267 0.00651 353 0.0238 0.00755 354 0.0288 0.00707 3550.00441 0.00132 356 0.0060 0.00762 357 0.0236 0.0106 358 0.0202 0.00919359 0.0208 0.0217 360 0.0957 0.0509 361 0.0357 0.0561 362 0.00969 0.0019363 0.0505 0.0114 364 0.365 0.11 365 0.0845 0.0463 366 0.00993 0.00295367 0.0183 0.00211 368 0.17 0.991 369 0.167 0.0933 370 0.169 0.115 3710.0286 0.0302 372 0.0227 0.0275 373 0.0152 0.00703 375 0.00888 0.00111376 0.0675 0.0161 377 0.0149 0.00159 378 0.241 2.0 379 1.47 2.0 3810.0233 0.0554 382 0.0229 0.0248 383 0.0158 2.0 384 0.928 0.436 3850.0824 0.0171 387 0.724 0.535 388 0.034 0.00126 389 0.0216 0.000575 3920.699 2.0 393 0.0495 0.0185 394 0.0205 0.0145 395 0.193 0.0243 396 0.0280.0175 397 0.412 0.888 398 0.0125 0.000722 399 0.00331 0.000381 4000.136 0.222 401 0.29 2.0 402 0.557 2.0 403 0.011 0.0029 404 0.01360.00375 405 0.00637 0.00534 406 0.29 2 407 0.0131 0.0726 408 0.003760.00101 409 0.0119 0.00103 410 0.0121 0.00393 411 0.121 2.0 413 0.00530.00292 414 0.34 0.0535 415 0.0128 0.0142 416 0.082 0.461 417 0.05060.83 418 0.0056 0.00352 419 0.00149 0.000489

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will be apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1. A compound of Formula I:

wherein: R is (a) an 8-, 9-, or 10-membered bicyclic heteroarylcomprising one heteroatom selected from N, S, and O, and one, two, orthree additional N atoms, wherein said bicyclic heteroaryl isunsubstituted or is substituted with one or more substituents selectedfrom the group consisting of deuterium, amino, alkylamino, dialkylamino,alkyl, halo, cyano, haloalkyl, hydroxy, hydroxyalkyl, and alkoxy, andwherein one or more N atoms of said bicyclic heteroaryl is optionally anN-oxide; or (b) a five- or six-membered nitrogen-linked heterocycloalkylring fused to a phenyl or monocyclic five- or six-membered heteroaryl,wherein said phenyl or heteroaryl is unsubstituted or is substitutedwith one or more substituents selected from the group consisting ofdeuterium, amino, alkylamino, dialkylamino, alkyl, halo, cyano,haloalkyl, hydroxy, hydroxyalkyl, and alkoxy; and R¹ is H,—(C₁₋₄alkylene)₀₋₁C(O)R^(a), —(C₁₋₄alkylene)₀₋₁CO₂R^(a),—(C₁₋₄alkylene)₀₋₁S(O)R^(a), —(C₁₋₄alkylene)₀₋₁SO₂R^(a), —C(O)NH(R^(a)),—C(O)N(R^(a))₂, or —C(O)C(O)NH(R^(a)); wherein each R^(a) isindependently (1) alkyl, unsubstituted or substituted with one or moreR^(m) substituents, wherein each R^(m) is independently selected fromthe group consisting of hydroxy, —NR^(b)R^(c), alkoxy, cyano, halo,—C(O)alkyl, —CO₂alkyl, —CONR^(b)R^(c), —S(O)alkyl, —SO₂alkyl,—SO₂NR^(b)R^(c), aryl, heteroaryl, cycloalkyl, heterocycloalkyl,phenoxy, and —O-alkyl-OH; wherein R^(b) is H or alkyl; R^(c) is H,alkyl, alkoxyalkyl, haloalkyl, —C(O)alkyl, —CO₂alkyl, —SO₂alkyl,—C(O)NH₂, or C(O)H; and each aryl, heteroaryl, cycloalkyl, andheterocycloalkyl group within R^(m) is unsubstituted or substituted withone or more substituents independently selected from the groupconsisting of alkyl, haloalkyl, hydroxy, —NR^(b)R^(c), alkoxy,haloalkoxy, cyano, halo, oxo, —C(O)alkyl, —CO₂alkyl, —C(O)—heterocycloalkyl, —CONR^(b)R^(c), —S(O)alkyl, —SO₂alkyl, —SO₂-haloalkyl,—SO₂NR^(b)R^(c), aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; wherein each alkyl or alkoxy is unsubstituted or substituted with—NR^(b)R^(c), heterocycloalkyl, heteroaryl, or —C(O)alkyl; and  eacharyl, heteroaryl, cycloalkyl, and heterocycloalkyl is unsubstituted orsubstituted with alkyl, halo, or —C(O)alkyl; (2) phenyl, cycloalkyl,heteroaryl, or heterocycloalkyl, each unsubstituted or substituted withone or more substituents selected from the group consisting of alkyl,haloalkyl, hydroxy, —NR^(b)R^(c), alkoxy, haloalkoxy, cyano, halo, oxo,—C(O)alkyl, —CO₂alkyl, —C(O)-heterocycloalkyl, —CONR^(b)R^(c),—S(O)alkyl, —SO₂alkyl, —SO₂-haloalkyl, —SO₂NR^(b)R^(c), aryl,heteroaryl, cycloalkyl, and heterocycloalkyl; wherein each alkyl oralkoxy is unsubstituted or substituted with —NR^(b)R^(c),heterocycloalkyl, heteroaryl, or —C(O)alkyl; and each aryl, heteroaryl,cycloalkyl, and heterocycloalkyl is unsubstituted or substituted withalkyl, halo, or —C(O)alkyl; or (3) —NR^(x)R^(y), where R^(x) is H oralkyl; and R^(y) is H, alkyl, alkoxyalkyl, haloalkyl, —C(O)alkyl,—CO₂alkyl, or —SO₂alkyl; R² and R³ are each independently H ordeuterium; and n is 1 or 2; or a stereoisomer thereof, or apharmaceutically acceptable salt of such a compound or stereoisomer. 2.The compound of claim 1, wherein R is an 8- or 9-membered heteroaryl,unsubstituted or substituted as described for claim
 1. 3. The compoundof claim 1, wherein R is:

each unsubstituted or substituted as described for claim
 1. 4. Thecompound of claim 1, wherein, R is a five- or six-memberednitrogen-linked heterocycloalkyl ring fused to an unsubstituted orsubstituted phenyl or monocyclic heteroaryl, as defined in claim
 1. 5.The compound of claim 1, wherein R is


6. The compound of claim 1, wherein R¹ is H, —C(O)R^(a), —CO₂R^(a),—S(O)R^(a), or —SO₂R^(a).
 7. (canceled)
 8. (canceled)
 9. The compound ofclaim 1, wherein R^(a) is methyl, ethyl, propyl, isopropyl, tert-butyl,isobutyl, isopentyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, triazoyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, isoindolinyl, azetidinyl, oxetanyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl,tetrahydropyranyl, or tetrahydrothiophenyl, each unsubstituted orsubstituted.
 10. The compound of claim 1, wherein R^(a) is phenyl,cycloalkyl, heteroaryl, or heterocycloalkyl, each unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of fluoro, oxo, methyl, —CONH₂, acetyl, —SO₂methyl,—C(O)-isopropyl, pyridazinyl, triazolyl, dimethylaminomethyl, cyano,methyl-triazolyl-methoxy, trifluoromethoxy, pyrrolidinylmethyl,acetylamino, tetrazolylmethyl, methyl-tetrazolyl-methyl,methyl-imidazolyl-methyl, —NHSO₂methyl, 1,1-dioxothiomorpholinyl,4-methyl-piperazinylmethyl, —NHCONH₂, —SO₂CF₃, morpholinylmethyl,imidazolyl, —SO₂NH₂, methylpiperidinyl, methyl-piperazinyl,—C(O)(4-methyl-piperazinyl), morpholinyl, trifluoromethyl, cyclopropyl,ethyl, isoxazolyl, tetrazolyl, isopropyl, phenyl, fluoro-phenyl,tert-butyl, benzyl, N-methylpyrrolidinyl, N-acetyl-pyrrolidinyl,isobutyl, propyl, methylpyrazolyl, trifluoroethyl, pyrimidinyl, oxo,acetyl, cyano, —CO₂-tert-butyl, and amino.
 11. The compound of claim 1,wherein R^(a) is alkyl, unsubstituted or substituted with one or moresubstituents selected from the group consisting of fluoro, tert-butoxy,—C(O)NMe₂, —NHCHO, methoxy, phenoxy, cyano, acetyl, hydroxy,—OCH₂C(CH₃)═OH, —NH(acetyl), and —N(Me)(acetyl).
 12. The compound ofclaim 1, wherein R¹ is —SO₂R^(a), where R^(a) is methyl, ethyl, phenyl,benzyl, or 2,2-dimethylpropyl.
 13. The compound of claim 1, wherein R¹is —C(O)NHR^(a), wherein R^(a) is methyl, ethyl, propyl, isopropyl,tertobutyl, cyclohexyl, —CH₂-cyclohexyl, oxetanyl, or methyloxetanyl, orR^(a) is a phenyl or benzyl group, each optionally substituted with oneor more substituents selected from the group consisting of cyano,methyl, fluoro, methoxy, and chloro.
 14. The compound of claim 1,wherein both R² and R³ are H.
 15. The compound of claim 1, which is acompound of Formula I-a:

wherein R, R¹, R², and R³ are as defined for Formula I; or astereoisomer thereof, or a pharmaceutically acceptable salt of such acompound or stereoisomer.
 16. A compound selected from the groupconsisting of:

tert-butyl 2-[(1,3- dihydropyrrolo[3,4- c]pyridine-2-carbonylamino)methyl]-8- azaspiro[2.5]octane-8- carboxylate;

tert-butyl 2-[(thieno[2,3- c]pyridine-2- carbonylamino)methyl]-8-azaspiro[2.5]octane-8- carboxylate;

tert-butyl 2-[(imidazo[1,2- a]pyrimidine-6- carbonylamino)methyl]-8-azaspiro[2.5]octane-8- carboxylate;

tert-butyl 2-[(furo[2,3- c]pyridine-2- carbonylamino)methyl]-8-azaspiro[2.5]octane-8- carboxylate;

tert-butyl 2-[(imidazo[1,2- a]pyridine-6- carbonylamino)methyl]-8-azaspiro[2.5]octane-8- carboxylate;

N-[[8-(3,3- dimethylbutanoyl)-8- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide;

N-[[8-(2-phenylacetyl)-8- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide

tert-butyl 2-[(1H-pyrrolo[3,2- c]pyridine-2- carbonylamino)methyl]-8-azaspiro[2.5]octane-8- carboxylate;

N-[[8- (cyclohexanecarbonyl)-8- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide;

N-[[8-(tetrahydropyran-4- carbonyl)-8- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide;

N-[(8-benzoyl-8- azaspiro[2.5]octan-2- yl)methyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide;

N-[[8-(2-methylpropanoyl)-8- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide;

N-[[8-(benzenesulfonyl)-8- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide

N-[(8-ethylsulfonyl-8- azaspiro[2.5]octan-2- yl)methyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide;

tert-butyl 2-[(1H- pyrazolo[3,4-b]pyridine-5- carbonylamino)methyl]-8-azaspiro[2.5]octane-8- carboxylate;

N-[(8-acetyl-8- azaspiro[2.5]octan-2- yl)methyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide;

N-[(8-methylsulfonyl-8- azaspiro[2.5]octan-2- yl)methyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide;

N-(8-azaspiro[2.5]octan-2- ylmethyl)-1H-pyrrolo[3.2-c]pyridine-2-carboxamide;

N-(8-azaspiro[2.5]octan-2- ylmethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide;

N-[(8-propanoyl-8- azaspiro[2.5]octan-2- yl)methyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide;

tert-butyl 2-((imidazo[1,2- a]pyridine-6- carboxamido)methyl)-7-azaspiro[3.5]nonane-7- carboxylate;

tert-butyl 2-[(imidazo[1,2- a]pyridine-6- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate;

tert-butyl 2-[(furo[2,3- c]pyridine-2- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate;

N-[[6-(3,3- dimethylbutanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide;

tert-butyl 2-[(1,3- dihydropyrrolo[3,4- c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate;

N-[[6-(2-imidazol-1-ylacetyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(4,4,4- trifluorobutanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(3- methylsulfonylphenyl)acetyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(3,3- dimethylbutanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(4-methylpiperazin- 1-yl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(3- cyanophenyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2-cyclopropylacetyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2-pyrrolidin-1- ylacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(3-methylisoxazol-5- yl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(1-piperidyl)acetyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2-tetrahydropyran-4- ylacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2-tetrahydrofuran-2- ylacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2-tert-butoxyacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(3-pyridyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-[1-(2,2,2- trifluoroethyl)-4- piperidyl]acetyl]-6-azaspiro[2.5]octan-2- yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide;

tert-butyl 2-[(imidazo[1,2- a]pyridine-6- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate;

tert-butyl 2-[(imidazo[1,2- a]pyridine-6- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate;

tert-butyl 2-[(furo[2,3- c]pyridine-2- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate;

tert-butyl 2-[(furo[2,3- c]pyridine-2- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate;

N-[[6-(3,3- dimethylbutanoyl)-6- azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(3-methylbutanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide;

N-[[6-(2-phenylacetyl)-6- azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

tert-butyl 2-[(1,3- dihydropyrrolo[3,4- c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate;

tert-butyl 2-[(1,3- dihydropyrrolo[3,4- c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate;

N-[[6-(2-pyrazin-2-ylacetyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2-morpholinoacetyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2-tetrahydropyran-2- ylacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2-pyrrolidin-1- ylpropanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(tert-butylamino)-2- oxo-acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[4-(dimethylamino)-4- oxo-butanoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1-methyl-5-oxo- pyrrolidine-3-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(2-oxopyrrolidin-1- yl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2,2- difluorocyclopropanecarbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(tetrahydrofuran-3- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(tetrahydropyran-4- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(tetrahydrofuran-2- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2-formamidoacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[3-(3,5- dimethylpyrazol-1- yl)propanoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1- carbamoylpyrrolidine-2- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(3- morpholinopropanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1,1-dioxothiolane-3- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(3,5- dimethylpyrazol-1-yl)acetyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1-acetylpyrrolidine-2- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2- methylsulfonylbenzoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[3-(1,2,4-triazol-4- yl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[4- [(dimethylamino)methyl] benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(4-acetamidobenzoyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1- methylsulfonylpiperidine-3- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1- methylsulfonylpiperidine-4- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2- morpholinopropanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1- methylsulfonylpyrrolidine-2- carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(3-oxoisoindolin-1- yl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1- carbamoylpiperidine-4- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1- carbamoylpiperidine-3- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(1,1-dioxothiolan-3- yl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(2,4-dioxopyrimidin- 1-yl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1-acetylpiperidine-4- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[4-(tetrazol-1- ylmethyl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[4- (methanesulfonamido)benzoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[4-(1,1-dioxo-1,4- thiazinan-4-yl)benzoyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[4-[(4-methylpiperazin- 1-yl)methyl]benzoyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-[(4-methylpiperazin- 1-yl)methyl]benzoyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[3-[(4-methylpiperazin- 1-yl)methyl]benzoyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[3-(4-methylpiperazin- 1-yl)propanoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1-isopropyl-5-oxo- pyrrolidine-3-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(3-oxopiperazin-1- yl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(3- methylsulfonylbenzoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(4- methylsulfonylbenzoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(4-ureidobenzoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(4-acetylpiperazin- 1-yl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[4-[(5-methyltetrazol-1- yl)methyl]benzoyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(pyridine-4-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(pyridine-2-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(oxazole-4-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1H-1,2,4-triazole-3- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1H-imidazole-4- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(pyrimidine-4- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(pyridine-3-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1H-pyrazole-3- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1-methylimidazole-4- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(3-methyl-1H- pyrazole-4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2-methylpyrazole-3- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(5-methyl-1H- pyrazole-3-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1-methylpyrazole-3- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(pyridazine-3- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(pyrimidine-5- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(pyrazine-2-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(pyridazine-4- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1-methylpyrazole-4- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1,5-dimethylpyrazole- 3-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2,5-dimethylpyrazole- 3-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(5-methylisoxazole-3- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(4-methyl-1,2,5- oxadiazole-3-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2-methylpyridine-3- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(4-methylpyridine-3- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2-methylpyridine-4- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(5-methylpyrazine-2- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(3-cyclopropyl-1H- pyrazole-5-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1-ethyl-5-methyl- pyrazole-4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(3,5- dimethylisoxazole-4- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1-ethylpyrazole-4- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(6-cyanopyridine-3- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2,4-dimethyloxazole- 5-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2-morpholinopyridine- 4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6- (cyclopropanecarbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[1-methyl-5- (trifluoromethyl)pyrazole-3- carbonyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(4-isoxazol-5-yl-1- methyl-pyrazole-3- carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2-acetamidopyridine- 4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[3-(tetrazol-1-yl)-1H- pyrazole-4-carbonyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(6-acetamidopyridine- 2-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(3-ethyl-5-methyl- isoxazole-4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(2-ethyl-5-methyl- pyrazole-3-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1-ethyl-3-methyl- pyrazole-4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(3-methylisoxazole-4- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-methyl-3-(3- methylpyrazol-1- yl)propanoyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1H-pyrazole-4- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(1-methylsulfonyl-4- piperidyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(4-methylmorpholine- 2-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[1-(2- methylpropanoyl)azetidine- 3-carbonyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1-acetylazetidine-3- carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(1-pyridazin-3- ylpyrrolidine-3-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(1-pyrimidin-2-yl-4- piperidyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(1-isopropyl-4- piperidyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(1-methyl-4- piperidyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide

N-[[6-[2-(3-methyloxetan-3- yl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide;

isopropyl 2-[(1,3- dihydropyrrolo[3,4- c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate;

N-[[6-[2-(2- cyanophenyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(3-methoxypropanoyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-[4- (trifluoromethylsulfonyl) phenyl]acetyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[3- [acetyl(methyl)amino]propanoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[2-(2-pyridyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[(4- cyanophenyl)carbamoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(m- tolylmethylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(p-tolylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(benzylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-[(2- fluorophenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(p- tolylmethylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine- 2-carboxamide;

N-[[6-(m-tolylmethylcarbamoyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(p-tolylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(benzylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[(2- fluorophenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(p-tolylmethylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[(4- fluorophenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[(2- methoxyphenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[(3- methoxyphenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[(3- fluorophenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[(4- methoxyphenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[(3,4- dichlorophenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1-adamantylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[(4- chlorophenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[(2- chlorophenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(ethylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[(2,4- dichlorophenyl)methylcarbamoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[2-(3-hydroxy-3-methyl- cyclobutyl)acetyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[2-(3-methyloxetan-3- yl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-[2-(2-pyridyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-[2-(3-pyridyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-[2-(3-cyanophenyl)acetyl]- 6-azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-[4-(1,2,4-triazol-1- yl)benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[2-(2-methylimidazol-1- yl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1,3,5-trimethylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(tert-butylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(isopropylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6- (cyclohexylmethylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(propylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(cyclohexylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(phenylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[2-(1-isopropyl-4- piperidyl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide;

N-[[6-(3-methylbutanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-[2-(4-pyridyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(2-cyanoacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

ethyl 2-[(1,3-dihydropyrrolo[3,4- c]pyridine-2- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate;

tert-butyl 2-[(1H-pyrrolo[3,2- c]pyridine-2- carbonylamino)methyl]-7-azaspiro[3.5]nonane-7- carboxylate;

tert-butyl 2-[(furo[2,3-c]pyridine- 2-carbonylamino)methyl]-7-azaspiro[3.5]nonane-7- carboxylate;

N-[[6-[2-(3-methyloxetan-3- yl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(2-cyclohexylacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(3-cyclohexylpropanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(2-morpholinoacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(3-phenylpropanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

tert-butyl 2-[(1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-7- azaspiro[3.5]nonane-7- carboxylate;

N-[[6-[2-(3,5- difluorophenyl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide;

N-[[6-[2-[3- (trifluoromethyl)phenyl]acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide;

N-[[6-(tert-butylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide;

[2.2,2-trideuterio-1,1- bis(trideuteriomethyl)ethyl] 2-[(1,3-dihydropyrrolo[3,4- c]pyridine-2- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate;

(2-methoxy-1,1-dimethyl-2-oxo- ethyl) 2-[(furo[2,3-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate;

N-[[6-[2-(3-cyanophenyl)acetyl]- 6-azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide;

N-[[6-[2-(4-cyanophenyl)acetyl]- 6-azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(phenylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-[3-(3-pyridyl)propanoyl]-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(benzylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[(6-benzylsulfonyl-6- azaspiro[2.5]octan-2-yl)methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(tert-butylcarbamoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(3,3-dimethylbutanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide;

N-[[6-(3,3-dimethylbutanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide;

(2-hydroxy-1,1-dimethyl-ethyl) 2- [(furo[2,3-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate;

N-[[6-[2-(4-cyanophenyl)acetyl]- 6-azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide;

(2-methoxy-1,1-dimethyl-ethyl) 2-[(1,3-dihydropyrrolo[3,4- c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate;

N-[[6-(2-tetrahydropyran-4- ylacetyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(1,3,5-trimethylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide;

N-[[6-(1-methylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide;

N-[[6-(1-isopropyl-3,5-dimethyl- pyrazole-4-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[1-(4-fluorophenyl)-3.5- dimethyl-pyrazole-4-carbonyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

(1-methylcyclobutyl) 2-[(1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate;

N-[[6-(3-morpholinopropanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(2,2-difluoro-2-phenyl- acetyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(3-methylpyridine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(3-methylpyridine-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(6-methylpyridine-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(6-methylpyridine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(4-methylpyridine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1H-benzimidazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(pyrrolo[1,2-c]pyrimidine-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1H-benzotriazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1H-pyrrolo[2,3-b]pyridine- 4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1H-indazole-4-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1H-benzimidazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(4-cyanobenzoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(3-cyanobenzoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[4-[(5-methyl-1,2,4- oxadiazol-3-yl)methoxy]benzoyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[4- (morpholinomethyl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[4-[(2-methylimidazol-1- yl)methyl]benzoyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[4- (trifluoromethoxy)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[4-(pyrrolidin-1- ylmethyl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[3-(1,2,4-triazol-1- ylmethyl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[2-(1,2,4-triazol-1- ylmethyl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[4-(1,2,4-triazol-1- ylmethyl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[3-(imidazol-1- ylmethyl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(4-imidazol-1-ylbenzoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[4-(1H-1,2,4-triazol-5- yl)benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(6-imidazol-1-ylpyridine-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[4-(trifluoromethyl)pyridine- 2-carbonyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[6-(trifluoromethyl)pyridine- 3-carbonyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(3-oxo-4H-1,4- benzoxazine-6-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(4-sulfamoylbenzoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[2-(imidazol-1- ylmethyl)benzoyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(quinoxaline-6-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1,6-naphthyridine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(2-methyl-1H- benzimidazole-5-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(3-acetamidobenzoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(3-acetamidopyridine-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(2,1,3-benzoxadiazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1,8-naphthyridine-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(isoquinoline-5-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(quinoxaline-2-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1,5-naphthyridine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1,8-naphthyridine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(isoxazole-5-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(3-methylbutanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

tert-butyl 2-[(4,6-dihydro-1H- pyrrolo[3,4-c]pyrazole-5-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate;

N-[[6-[2-(1,4-dimethyl-4- piperidyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[2-(3-hydroxy-3-methyl- cyclobutyl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide;

N-[[6-[2-(3-pyridyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide;

N-[[6-[2-(4-pyridyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide;

N-[[6-(1,3-dimethylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide;

N-[[6-[4-(2-methyltetrazol-5- yl)benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(4,6-dimethylpyridine-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(4-oxopentanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2 carboxamide;

N-[[6-(4-hydroxy-4-methyl- pentanoyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(3-hydroxy-3-methyl- butanoyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[2-(2-pyridyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide;

N-[[6-(2-pyrimidin-2-ylacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(2-pyrazin-2-ylacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(3-thiazol-2-ylpropanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(2-phenoxyacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(3-tetrahydropyran-4- ylpropanoyl)-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide;

N-[[6-(4-methylpyridine-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide;

N-[[6-(3,5-dimethyl-1H-pyrazole- 4-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide;

N-[[6-(1,3,5-trimethylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide;

N-[[6-(1-tert-butyl-3,5-dimethyl- pyrazole-4-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1-benzyl-3,5-dimethyl- pyrazole-4-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(5-tert-butyl-2-methyl- pyrazole-3-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(2-ethylpyrazole-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(2-tert-butyl-4-methyl- pyrazole-3-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(2,4-dimethylpyrazole-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1,3,5-trimethylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1,3,5-trimethylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1H-indazole-3-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[1-(1-isopropylpyrrolidin-3- yl)pyrazole-4-carbonyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[1-(1-acetylpyrrolidin-3- yl)pyrazole-4-carbonyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[5-(1,3-dimethylpyrazol-4- yl)isoxazole-3-carbonyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

tert-butyl 3-[2-[(furo[2,3- c]pyridine-2- carbonylamino)methyl]-6-azaspiro[2.5]octane-6-carbonyl]- 4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-carboxylate;

N-[[6-[1-(1-methylpyrrolidin-3- yl)pyrazole-4-carbonyl]-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(2-tert-butyl-5-methyl- pyrazole-3-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(2-methylimidazo[1,2- a]pyridine-3-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(6-methyl-1H- benzimidazole-2-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(5-methylimidazo[1,2- a]pyridine-2-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(6-fluoro-1H-indazole-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(pyrazolo[1,5-a]pyrimidine- 2-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1-ethyl-3,5-dimethyl- pyrazole-4-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(6-methylimidazo[1,2- a]pyridine-2-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(imidazo[1,2-a]pyridine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(5-isopropylisoxazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(3-isobutyl-1H-pyrazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(imidazo[1,2-a]pyrimidine- 2-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(pyrazolo[1,5-a]pyrimidine- 3-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(3-tert-butyl-1H-pyrazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(5-isopropyl-1H-pyrazole- 3-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(3-isopropyl-1H-pyrazole- 4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(2-isopropylpyrazole-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(5-ethyl-2-methyl-pyrazole- 3-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(5-cyclopropylisoxazole-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(5-cyclopropylisoxazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(3,5-dimethyl-1H-pyrazole- 4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1,5-dimethylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(4-methyloxazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(3-cyclopropyl-1H- pyrazole-4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1,4,5,6- tetrahydrocyclopenta[c]pyrazole- 3-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(2,5-dimethyloxazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1,3-dimethylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(oxazole-5-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(isoxazole-4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(1H-imidazole-2-carbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[4-(4-methylpiperazin-1- yl)benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(3H-imidazo[4,5-b]pyridine- 6-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(5-methylpyridine-2- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[4-[(4-methylpiperazin-1- yl)methyl]benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide;

N-[[6-[3-[(4-methylpiperazin-1- yl)methyl]benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide;

N-[[6-[4- [(dimethylamino)methyl]benzoyl]- 6-azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide;

N-[[6-[4-[(4-methylpiperazin-1- yl)methyl]benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide;

N-[[6-(1,5-dimethylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide;

N-[[6-(2,2- dimethylcyclopropanecarbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide;

(3-methyloxetan-3-yl) 2-[(1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate;

(2-hydroxy-1,1-dimethyl-ethyl) 2- [(1,3-dihydropyrrolo[3,4-c]pyridine-2- carbonylamino)methyl]-6- azaspiro[2.5]octane-6-carboxylate;

N-[[6-(4-methylpyridine-3- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide;

N-[[6-(3-cyclopropyl-1H- pyrazole-5-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide;

N-[[6-(4-isoxazol-5-yl-1-methyl- pyrazole-3-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide;

N-[[6-(2,4-dimethyloxazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide;

N-[[6-[2-(1,4-dimethyl-4- piperidyl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide;

N-[[6-[2-(2-cyanophenyl)acetyl]- 6-azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

(2-acetamido-1,1-dimethyl-ethyl) 2-[(1,3-dihydropyrrolo[3,4-c]pyridine-2- carbonylamino)methyl]-6- azaspiro[2.5]octane-6-carboxylate;

N-[[6-(2-thiazol-2-ylacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(4-hydroxy-4-methyl- pentanoyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide;

N-[[6-[(3-methyloxetan-3- yl)carbamoyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide;

N-[[6-[4-(4-methylpiperazin-1- yl)benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide;

N-[[6-[4-(4-methylpiperazin-1- yl)benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide;

N-[[6-(2,2- dimethylcyclopropanecarbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide;

N-[[6-(1,3,5-trimethylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide;

N-[[6-(1,3,5-trimethylpyrazole-4- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide;

tert-butyl 2-[[(1,1,3,3- tetradeuteriopyrrolo[3,4- c]pyridine-2-carbonyl)amino]methyl]-6- azaspiro[2.5]octane-6- carboxylate;

N-[[6-(3-cyclopropyl-1H- pyrazole-5-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide;

N-[[6-(4-isoxazol-5-yl-1-methyl- pyrazole-3-carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide;

N-[[6-(2,4-dimethyloxazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide;

N-[[6-(2,2- dimethylcyclopropanecarbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[4-(4-methylpiperazine-1- carbonyl)benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide;

N-[[6-(2,2- dimethylcyclopropanecarbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

(3-methyltetrahydrofuran-3-yl) 2- [(1,3-dihydropyrrolo[3,4-c]pyridine-2- carbonylamino)methyl]-6- azaspiro[2.5]octane-6-carboxylate;

(2-hydroxy-2-methyl-propyl) 2- [(1,3-dihydropyrrolo[3,4- c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate;

N-[[6-(2,2- dimethylcyclopropanecarbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(2,2- dimethylpropylsulfonyl)-6- azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(2,2- dimethylpropylsulfonyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2-c]pyridine-2- carboxamide;

N-[[6-(2,2- dimethylpropylsulfonyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(4,4,4-trifluorobutanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

tert-butyl 2-[(pyrazolo[1,5- b]pyridazine-5- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate;

N-[[6-(2,4-dimethyloxazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-(2,4-dimethyloxazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]furo[2,3-c]pyridine-2- carboxamide;

N-[[6-[2-(2-hydroxy-2-methyl- propoxy)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide;

N-[[6-[2-methyl-4- (trifluoromethyl)thiazole-5-carbonyl]-6-azaspiro[2.5]octan- 2-yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2- carboxamide;

N-[[6-(2,2- dimethylcyclopropanecarbonyl)- 6-azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

tert-butyl 2-[(imidazo[1,2- a]pyridin-6- ylmethylcarbamoylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate;

N-[[6-[2-(2-hydroxy-2-methyl- propoxy)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide;

N-[[6-[2-(6-amino-3- pyridyl)acetyl]-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(morpholine-4-carbonyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-[5-(trifluoromethyl)-1H- pyrazole-3-carbonyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide;

N-[[6-(4-hydroxy-4-methyl- pentanoyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide;

N-[[6-[4-(trifluoromethyl)pyridine- 3-carbonyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide;

N-[[6-[2-(4- methyltetrahydropyran-4- yl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-[2-(3-hydroxy-3-methyl- cyclobutyl)acetyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide;

(2-hydroxy-2-methyl-propyl) 2- [(1H-pyrrolo[3,2-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate;

tert-butyl 2-[(imidazo[1,2- b]pyridazine-6- carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate;

N-[[6-[2-[4-methyl-1-(2,2,2- trifluoroethyl)-4-piperidyl]acetyl]-6-azaspiro[2.5]octan-2- yl]methyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide;

N-[[6-(2,4-dimethylthiazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide;

N-[[6-[4-(1-methyl-4- piperidyl)benzoyl]-6-azaspiro[2.5]octan-2-yl]methyl]- 1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide;

tert-butyl 2-[[(6-amino-1,3- dihydropyrrolo[3,4-c]pyridine-2-carbonyl)amino]methyl]-6- azaspiro[2.5]octane-6- carboxylate;

N-[[6-(2-pyrimidin-5-ylacetyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

1,1,3,3-tetradeuterio-N-[[6-(3- methylbutanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]pyrrolo[3,4-c]pyridine- 2-carboxamide;

(3-methyloxetan-3-yl) 2- [[(1,1,3,3- tetradeuteriopyrrolo[3,4-c]pyridine-2- carbonyl)amino]methyl]-6- azaspiro[2.5]octane-6-carboxylate;

1,1,3,3-tetradeuterio-N-[[6-(2,4- dimethyloxazole-5-carbonyl)-6-azaspiro[2.5]octan-2- yl]methyl]pyrrolo[3,4-c]pyridine- 2-carboxamide;

N-[(6-benzoyl-6- azaspiro[2.5]octan-2- yl)methyl]furo[2,3-c]pyridine-2-carboxamide;

N-[[(2S)-6-(3-methylbutanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[(2R)-6-(3-methylbutanoyl)-6- azaspiro[2.5]octan-2-yl]methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide;

N-[[6-(4-methyloxazole-5- carbonyl)-6-azaspiro[2.5]octan-2-yl]methyl]-1,3- dihydropyrrolo[3,4-c]pyridine-2- carboxamide;

isopropyl 2-[(furo[2,3-c]pyridine- 2-carbonylamino)methyl]-6-azaspiro[2.5]octane-6- carboxylate;

(3-methyloxetan-3-yl) 2- [(furo[2,3-c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate;

N-[(6-benzoyl-6- azaspiro[2.5]octan-2-yl)methyl]-1,3-dihydropyrrolo[3,4- c]pyridine-2-carboxamide; and

(3-methyloxetan-3-yl) (2S)-2- [(1,3-dihydropyrrolo[3,4- c]pyridine-2-carbonylamino)methyl]-6- azaspiro[2.5]octane-6- carboxylate;

and stereoisomers thereof, and pharmaceutically acceptable salts of suchcompounds and stereoisomers.
 17. A pharmaceutical compositioncomprising: (a) an effective amount of at least one compound of claim 1;and (b) a pharmaceutically acceptable carrier.
 18. The pharmaceuticalcomposition of claim 17, further comprising a rescuing agent selectedfrom the group consisting of nicotinamide, nicotinic acid, andnicotinamide mononucleotide (NMN), or therapeutically effective amountsof one or more additional adjunctive active agents, wherein said one ormore additional adjuctive active agents are selected from the groupconsisting of cytotoxic agent, cisplatin, doxorubicin, taxotere, taxol,etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, theepothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide,cyclophosphamide, SCH 66336, tipifarnib (Zarnestra®), R115777, L778,123,BMS 214662, Iressa®, Tarceva®, C225, GLEEVEC®, Intron®, Peg-Intron®,aromatase combinations, ara-C, adriamycin, cytoxan, gemcitabine, Uracilmustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman,Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine,Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine,6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin,leucovirin, oxaliplatin (ELOXATIN®), Pentostatine, Vinblastine,Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin,Doxorubicin, Epirubicin, Idarubicin, Mithramycin™, Deoxycoformycin,Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol,Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone,Dromostanolone propionate, Testolactone, Megestrol acetate,Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone,Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine,Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene,goserelin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane,Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole,Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin,herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine,Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan,Trastuzumab, Lerozole, Fulvestrant, Exemestane, Ifosfomide, Rituximab,C225, Campath, leucovorin, and dexamethasone, bicalutamide, carboplatin,chlorambucil, cisplatin, letrozole, megestrol, valrubicin, vinblastineand NIASPAN®.
 19. (canceled)
 20. (canceled)
 21. (canceled)
 22. A methodof treating a subject suffering from or diagnosed with a disease ormedical condition mediated by NAMPT activity, comprising administeringto the subject in need of such treatment an effective amount of at leastone compound of claim
 1. 23. The method of claim 22, wherein the diseaseor medical condition is a solid or liquid tumor, non-small cell lungcancer, leukemia, lymphoma, ovarian cancer, glioma, breast cancer,uterine cancer, colon cancer, cervical cancer, lung cancer, prostatecancer, skin cancer, rhino-gastric tumors, colorectal cancer, CNScancer, bladder cancer, pancreatic cancer, Hodgkin's disease, rheumatoidarthritis, diabetes, atherosclerosis, sepsis, aging or inflammation. 24.The method of claim 22, further comprising administering to the subjectan effective amount of a rescuing agent selected from the groupconsisting of nicotinamide, nicotinic acid, and nicotinamidemononucleotide (NMN), or at least one compound selected from the groupconsisting of: a cytotoxic agent, cisplatin, doxorubicin, taxotere,taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel,docetaxel, the epothilones, tamoxifen, 5-fluorouracil, methoxtrexate,temozolomide, cyclophosphamide, SCH 66336, tipifarnib (Zarnestra®),R115777, L778,123, BMS 214662, Iressa®, Tarceva®, C225, GLEEVEC®,Intron®, Peg-Intron®, aromatase combinations, ara-C, adriamycin,cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, leucovirin, oxaliplatin(ELOXATIN®), Pentostatine, vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mithramycin™, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,Ifosfomide, Rituximab, C225, Campath, leucovorin, dexamethasone,bicalutamide, chlorambucil, letrozole, megestrol, valrubicin,vinblastine, and NIASPAN®.
 25. (canceled)
 26. (canceled)